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<body id="Nexus-615" lang="en-GB">
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			<p class="Type-of-Article">&nbsp;</p>
			<p class="Type-of-Article"><span class="CharOverride-1">Review Article</span></p>
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			<p class="title- ParaOverride-1">&nbsp;</p>
			<p class="title- ParaOverride-1">Emerging Role of Regulatory T Cells in Heterologous Infections</p>
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			<p class="Affiliations ParaOverride-1">&nbsp;</p>
			<p class="Affiliations ParaOverride-1"><span class="CharOverride-2">1</span>Department of Veterinary Physiology and Biochemistry, Lala Lajpat Rai University of Veterinary and Animal Sciences, Hisar, Haryana 125004, India; <span class="CharOverride-2">2</span>Virology Laboratory, <span class="CharOverride-2"> </span>Division of Animal Health, Central Institute for Research on Goats, Indian Council of Agricultural Research, Makhdoom, P.O.-Farah, Mathura, UP-281122, India.</p>
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			<p class="Authors"><span class="CharOverride-3">Shalini Sharma</span><span class="CharOverride-4">1*</span><span class="CharOverride-3">, Naveen Kumar</span><span class="CharOverride-4">2</span></p>
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			<p class="Abstract ParaOverride-1">&nbsp;</p>
			<p class="Abstract ParaOverride-1"><span class="CharOverride-5">Abstract</span> | Prior immunity can result in complete protection against a homologous agent. In the real world, however, each individual experiences multiple infections. Immune memory responses that are generated in an individual as a consequence of an initial or primary infection has been convincingly shown to influence the immune response and the course of infection of subsequent, unrelated pathogen challenge, by a process known as heterologous immunity. The fact that the host’s history of previous infections cannot be altered warrants our current understanding of the cellular mediators involved and the roles they play in regulating heterologous immunity. Several cellular mediators such as CD4, CD8T cells and various innate immune cells participate in mediating heterologous immunity. Regulatory T cells are an important subset of CD4T cells and here in this review we attempt to discuss our current understanding on the role of regulatory T cells (Tregs) in heterologous immune responses.</p>
		  <p class="Abstract ParaOverride-1">&nbsp;</p>
			<p class="Abstract ParaOverride-1"><span class="CharOverride-5">Keywords </span>| <span lang="en-US">Regulatory T cells, Heterologous infection</span></p>
		  <p class="Abstract ParaOverride-1">&nbsp;</p>
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			<p class="Editor----Citation"><span class="CharOverride-7">Editor</span> | Ruchi Tiwari, College of Veterinary Sciences, Department of Veterinary Microbiology and Immunology Uttar Pradesh Pandit Deen Dayal Upadhayay Pashu Chikitsa, Vigyan Vishvidhyalaya Evum Go-Anusandhan Sansthan (DUVASU), Mathura (U.P.) – 281001, India.</p>
			<p class="Editor----Citation"><span class="CharOverride-7">Special Issue</span>| 2 (2015) “Reviews on Trends and Advances in Safeguarding Terrestrial /Aquatic Animal Health and Production”</p>
			<p class="Editor----Citation"><span class="CharOverride-5">Received</span> | January 12, 2015; <span class="CharOverride-5">Revised</span> | February 05, 2015; <span class="CharOverride-5">Accepted</span> | February 07, 2015; <span class="CharOverride-5">Published</span> | February 12, 2015&#9;&#9;</p>
			<p class="Editor----Citation"><span class="CharOverride-5">*Correspondence</span> | Shalini Sharma, Lala Lajpat Rai University of Veterinary and Animal Sciences, Hisar, Haryana, India; <span class="CharOverride-5">Email:</span> ssharma3@utk.edu</p>
			<p class="Editor----Citation"><span class="CharOverride-5">Citation </span>| Sharma S, Kumar N (2015). Emerging role of regulatory T cells in heterologous infections. Adv. Anim. Vet. Sci. 3(2s): 25-31.  </p>
			<p class="Editor----Citation"><span class="CharOverride-7">DOI</span> | <a href="http://dx.doi.org/10.14737/journal.aavs/2015/3.2s.25.31"><span class="Hyperlink">http://dx.doi.org/10.14737/journal.aavs/2015/3.2s.25.31</span></a></p>
			<p class="Editor----Citation"><span class="Editor---Citation CharOverride-5" lang="en-US">ISSN </span><span class="Editor---Citation CharOverride-5" lang="en-US">(</span><span class="Editor---Citation CharOverride-5" lang="en-US">Online</span><span class="Editor---Citation CharOverride-5" lang="en-US">) | 2307-8316; <span class="Editor---Citation CharOverride-5" lang="en-US">ISSN </span><span class="Editor---Citation CharOverride-5" lang="en-US">(Print) </span> | 2309-3331</p>
			<p class="Editor----Citation"><span class="CharOverride-7">Copyright </span>© 2015 Sharma et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</p>
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			<p class="Heading-1--Introduction----">&nbsp;</p>
			<p class="Heading-1--Introduction----">&nbsp;</p>
		  <p class="Heading-1--Introduction----">HETEROLOGOUS IMMUNITY </p>
			<p class="Caps-on-First-Para ParaOverride-1">&nbsp;</p>
			<p class="Caps-on-First-Para ParaOverride-1"><span class="_idGenDropcap-1">A </span>very important and distinguishable feature of adaptive immunity is the generation of memory responses (<a href="#Farber-DL--2005-."><span class="Hyperlink">Farber, </span><span class="Hyperlink CharOverride-10">2005</span></a><span class="CharOverride-11">). Immune responses generated against a prior infectious agent can alter the immune response and the infection pattern of subsequent, unrelated pathogens by a process commonly defined as heterologous immunity (</span><a href="#Martin-SF--2014-."><span class="Hyperlink CharOverride-10">Martin, 2014</span></a><span class="CharOverride-11">; </span><a href="#Sharma-S--Thomas-PG--2014-."><span class="Hyperlink CharOverride-10">Sharma and Thomas, 2014</span></a><span class="CharOverride-11">). The outcome of heterologous infection can vary from good that is providing immunity to bad meaning resulting in a net immunopathology. The sequence of infections in heterologous infections may vary for example the infections can occur concurrently or sequentially. In a setting of infections with different strains of a similar pathogen or distinct pathogens are often classiﬁed as “coinfections” or super infections (</span><a href="#Selin-LK--Wlodarczyk-MF--Kraft-AR--Nie-S--Kenney-LL--Puzone-R--Celada-F--2011-."><span class="Hyperlink CharOverride-10">Selin et al., 2011</span></a><span class="CharOverride-11">; </span><a href="#Sharma-S--Thomas-PG--2014-."><span class="Hyperlink CharOverride-10">Sharma and Thomas, 2014</span></a><span class="CharOverride-11">).</span></p>
		  <p class="Caps-on-First-Para ParaOverride-1">&nbsp;</p>
			<p class="Heading-1--Introduction----">CD4T CELLS AS MEDIATORS OF HETEROLOGOUS IMMUNITY</p>
		  <p class="Heading-1--Introduction----">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">The CD4 T cell plays a plays a very prominent role in providing protection against viral infections and are also involved in the development of memory B cells and CD8 T cells (<a href="#Crotty-S--Ahmed-R--2004-."><span class="Hyperlink">Crotty and Ahmed, 2004</span></a>; <a href="#Konishi-E--2013-"><span class="Hyperlink">Konishi, 2013;</span></a> <a href="#Sun-JC--Ugolini-S--Vivier-E--2014-."><span class="Hyperlink">Sun et al., 2014</span></a>; <a href="#Zinkernagel-RM--2002-.-O"><span class="Hyperlink">Zinkernagel, 2002</span></a>). CD8 T cells require CD4T cell help and this is important for primary and/or memory responses to some bacterial and viral infections (<a href="#Bevan-MJ--2004-."><span class="Hyperlink">Bevan, 2004</span></a>; <a href="#Slifka-MK--2004-."><span class="Hyperlink">Slifka, 2004</span></a>; <a href="#Wodarz-D--2003-."><span class="Hyperlink">Wodarz, 2003</span></a>). When we talk in context of heterologous immunity, CD4 T cells can play a protective role or it can worsen the course of infection resulting in immunopathology (<a href="#Damjanovic-D--Small-CL--Jeyanathan-M--McCormick-S--Xing-Z--2012-."><span class="Hyperlink">Damjanovic et al., 2012</span></a>). For instance the adoptive transfer of CD8 and CD4 subsets from LCMV immune mice into naive mice resulted in heterologous immunity upon subsequent infections with Pichinde virus or Vaccinia virus (<a href="#Selin-LK--Varga-SM--Wong-IC--Welsh-RM--1998-."><span class="Hyperlink">Selin et al., 1998</span></a>). But we still lack the literature on the role of CD4T cells especially in the settings of various types of heterologous infections.</p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">CD4T cells have been shown to protect against heterologous infections in a bystander manner. For example a study with BCG strain of Mycobacterium bovis (a vaccine against tuberculosis) suggested that immunization of mice against the BCG strain of Mycobacterium bovis also protected the animals against challenge with Vaccinia virus (VV), belonging to family <span class="CharOverride-14">Poxviridae</span>. CD4T cells mediated this protection through production of IFN<span class="CharOverride-15">γ</span>.</p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">When an exacerbated immune response is generated, the immune system has developed several mechanisms to regulate these excessive immune responses that may cause pathology and autoimmune disease. These regulative mechanisms  include existence of regulatory T cells (<a href="#Belkaid-Y--Piccirillo-CA--Mendez-S--Shevach-EM--Sacks-DL--2002-"><span class="Hyperlink">Belkaid et al., 2002</span></a>; <a href="#Suvas-S--Kumaraguru-U--Pack-CD--Lee-S--Rouse-BT--2003-"><span class="Hyperlink">Suvas et al., 2003</span></a>), certain inhibitory interactions such as Tim3/Galectin 9 inhibitory interaction (<a href="#Belkaid-Y--Piccirillo-CA--Mendez-S--Shevach-EM--Sacks-DL--2002-"><span class="Hyperlink">Belkaid et al., 2002</span></a>; <a href="#Kuchroo-VK--Meyers-JH--Umetsu-DT--DeKruyff-RH--2006-"><span class="Hyperlink">Kuchroo et al., 2006</span></a>;<span class="Hyperlink"> </span><a href="#Kuchroo-VK--Dardalhon-V--Xiao-S--Anderson-AC--2008-."><span class="Hyperlink">Kuchroo et al., 2008</span></a>; <a href="#Sharma-S--Sundararajan-A--Suryawanshi-A--Kumar-2011"><span class="Hyperlink">Sharma et al., 2011</span></a>; <a href="#Su-EW--Bi-S--Kane-LP--2011-"><span class="Hyperlink">Su et al., 2011</span></a>; <a href="#Zhu-C--Anderson-AC--Schubart-A--Xiong-H--Imitola-J--Khoury-SJ--Zheng-XX--Strom-TB--Kuchroo-VK--2005"><span class="Hyperlink">Zhu et al., 2005</span></a>), PD1-PDL1 axis (<a href="#Rouse-BT--Sehrawat-S--2010-."><span class="Hyperlink">Rouse and Sehrawat, 2010</span></a>), CTLA-4 and CD80/86 (<a href="#Rouse-BT--Sehrawat-S--2010-."><span class="Hyperlink">Rouse and Sehrawat, 2010</span></a>) interactions. </p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Heading-1--Introduction----">REGULATORY  T CELLS </p>
		  <p class="Heading-1--Introduction----">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">Tregs are an important subset of CD4 T cells (<a href="#La-Cava-A--Van-Kaer-L--Fu-Dong-S--2006-."><span class="Hyperlink">La Cava et al., 2006</span></a>). The Tregs that develop in the thymus are known as naturally occurring Treg cells and the adaptive Tregs that are induced by various stimulations such as an antigen (<a href="#Benoist-C--Mathis-D--2012-."><span class="Hyperlink">Benoist and Mathis, 2012</span></a>; <a href="#French-M--Kinter-A--2012-"><span class="Hyperlink">French and Kinter, 2012</span></a>; <a href="#Robertson-SJ--Hasenkrug-KJ--2006-"><span class="Hyperlink">Robertson and Hasenkrug, 2006</span></a>; <a href="#Rouse-BT--Sarangi-PP--Suvas-S--2006-."><span class="Hyperlink">Rouse et al., 2006</span></a>). Naturally occurring CD4+CD25+ regulatory T cells have been shown to constitute 5–15% of peripheral CD4+ T in both mice and humans (<a href="#Sakaguchi-S--2003-"><span class="Hyperlink">Sakaguchi, 2003</span></a>). A large body of literature suggests that the severity of many immune inflammatory reactions are regulated or controlled by Tregs (<a href="#Suvas-S--Rouse-BT--2006-."><span class="Hyperlink">Suvas and Rouse, 2006</span></a>). The Tregs acts to limit or suppress the immune response generated against a pathogen (<a href="#Suvas-S--Azkur-AK--Kim-BS--Kumaraguru-U--Rouse-BT--2004-"><span class="Hyperlink">Suvas et al., 2004</span></a>). We need this Treg mediated suppression to prevent the collateral tissue damage that might occur due to the excessive immune response generated against the pathogen (<a href="#Sehrawat-S--Suvas-S--Sarangi-PP--Suryawanshi-A--Rouse-BT--2008-"><span class="Hyperlink">Sehrawat et al., 2008</span></a>). Thus Tregs greatly influence the magnitude of a T cell mediated immune response to an acute viral infection (<a href="#Sharma-S--Rajasagi-NK--Veiga-Parga-T--Rouse-BT--2014-."><span class="Hyperlink">Sharma et al., 2014</span></a>; <a href="#Suvas-S--Kumaraguru-U--Pack-CD--Lee-S--Rouse-BT--2003-"><span class="Hyperlink">Suvas et al., 2003</span></a>) particularly those that express FoxP3.</p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">Infections or challenge with the pathogens may signal Treg expansion and this Treg expansion could further influence the magnitude and also the pattern of the immune response. Thus in such cases immune responses against a pathogen and responses to vaccines are elevated if the Treg response is modulated (<a href="#Rouse-BT--Suvas-S--2004-."><span class="Hyperlink">Rouse and Suvas, 2004</span></a>; <a href="#Sehrawat-S--Suvas-S--Sarangi-PP--Suryawanshi-A--Rouse-BT--2008-"><span class="Hyperlink">Sehrawat et al., 2008</span></a>; <a href="#Suvas-S--Azkur-AK--Kim-BS--Kumaraguru-U--Rouse-BT--2004-"><span class="Hyperlink">Suvas et al., 2004</span></a>). </p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">The magnitude of the Treg response in different individuals may also explain in some circumstances the differential outcome of infection with chronic infection like hepatitis (<a href="#Rouse-BT--Sehrawat-S--2010-."><span class="Hyperlink">Rouse and Sehrawat, 2010</span></a>). In case of persistent infections where there is huge tissue damage, the Treg response can improve the outcome and diminish the pathology (<a href="#Sehrawat-S--Rouse-BT--2011-."><span class="Hyperlink">Sehrawat and Rouse, 2011</span></a>). In many studies the Treg response to pathogens is assumed to consist mainly or predominately of antigen specific Tregs (<a href="#Bedoya-F--Cheng-GS--Leibow-A--Zakhary-2013"><span class="Hyperlink">Bedoya et al., 2013</span></a>), but there are some examples to cite where the involvement of Tregs is not antigen speific (<a href="#Maizels-RM--Balic-A--Gomez-Escobar-N--Nair-M--Taylor-MD--Allen-JE--2004-."><span class="Hyperlink">Maizels et al., 2004</span></a>; <a href="#Telford-G--Wheeler-DJ--Appleby-P--Bowen-JG--Pritchard-DI--1998-"><span class="Hyperlink">Telford et al., 1998</span></a>; <a href="#Bedoya-F--Cheng-GS--Leibow-A--Zakhary-2013"><span class="Hyperlink">Bedoya et al., 2013</span></a>) and a recent study has shown a possible mechanism of generation of non-antigen specific Tregs (<a href="#Sharma-S--Rajasagi-NK--Veiga-Parga-T--Rouse-BT--2014-."><span class="Hyperlink">Sharma et al., 2014</span></a>).</p>
			<p class="Body-Text ParaOverride-1">&nbsp;</p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Heading-1--Introduction----">REGULATORY T CELLS IN HETEROLOGOUS INFECTIONS</p>
		  <p class="Heading-1--Introduction----">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">Here we discuss the Treg cells expanded during past infections that can potentially modulate the characteristics of effector T-cell responses and immunopathology during subsequent heterologous infections. The influence of natural Treg cells may favourably affect the outcome or can be harmful to the host (<a href="#Page-KR--Scott-AL--Manabe-YC--2006-"><span class="Hyperlink">Page et al., 2006</span></a>). However, the outcome of an infection (viral) may be affected by several other factors such as the stage of infection (<a href="#Figure-1-"><span class="Hyperlink">Figure 1A</span></a>, <a href="#Figure-1-"><span class="Hyperlink">1B</span></a> and <a href="#Figure-1-"><span class="Hyperlink">1C</span></a>), dose of the pathogen and genotype and immunological status of the host and also the presence of various other diseases and infections (<a href="#Belkaid-Y--Rouse-BT--2005-"><span class="Hyperlink">Belkaid and Rouse, 2005</span></a>).</p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			
            <div class="pt" > <a href="http://nexusacademicpublishers.com/uploads/figures/20150214150346.png" target="new"><img class="img_display" src="http://nexusacademicpublishers.com/uploads/figures/20150214150346.png" width="80" height="80"></a>
            
           <p class="Figure--and-Table-Heading ParaOverride-1"><span class="CharOverride-5"><a id="Figure-1-"></a>Figure 1:</span><a href="http://nexusacademicpublishers.com/uploads/figures/20150214150346.png"> Outcome of infection following heterologous viral infections is dependent on the stages of ongoing immune response to a previously encountered pathogen</a></p>
       </div>

		  <p class="Figure--and-Table-Heading ParaOverride-1"> (<span class="CharOverride-5">A</span>) If the infections with the viruses (here for example 2 virus system) occurs at the same time, the outcome could be enhanced immunopathology possibly due to the immune responses to both the viruses reaching the peak at the same time. (<span class="CharOverride-5">B</span>) Prior infection can result in activation of APC and the new incoming infection at this stage encounters mature APC, efficient antigen presentation and faster disease progression. Also the new incoming pathogen creates a strong antiviral state that might result in reduced viral loads of first pathogen. (<span class="CharOverride-5">C</span>) Upon activation APC’s secrete cytokines that results in T helper subset differentiation and the incoming pathogen at this stage encounters a polarized immune response. Encounter with Th1 type of immune response can provide bystander protection or enhanced imunopathology whereas T regs (<span class="CharOverride-5">D</span>) can result in suppression of immune responses to incoming pathogen, which may be protective or pathogenic. The outcome of heterologous viral infections however, depends on the type and sequence of viruses.</p>
		  <p class="Figure--and-Table-Heading ParaOverride-1">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">Although the role of Tregs has not been extensively evaluated in co-infection models, however several studies in hetrologous infections suggests that Tregs induced during one infection (<a href="#Figure-1-"><span class="Hyperlink">Figure 1D</span></a>) can lead to suppression of bystander responses (<a href="#Page-KR--Scott-AL--Manabe-YC--2006-"><span class="Hyperlink">Page et al., 2006</span></a>). The First evidence that depleting Tregs prior to viral infection enhances CD8T cell responses to subsequent viral infection came from the studies by <a href="#Suvas-S--Kumaraguru-U--Pack-CD--Lee-S--Rouse-BT--2003-"><span class="Hyperlink">Suvas et al. (2003)</span></a>. Their study demonstrated that depletion of Tregs resulted in increased activation and proliferation of Herpes Simplex virus (HSV-1) specific CD8T cells and this effect was observed both in the acute and memory phases of the immune response. These findings were very important in terms of explaining the phenomenon of diminished immunity during a viral infection or other infectious agents and suggested the fact that vaccine responses can be improved by Treg manipulation. This study also suggested how viral infection might temporarily diminish immunity to other infectious agents and thus their application to vaccines. Thus, controlling suppressor effects of regulatory T cells at the time of vaccination could result in more effective immunity.</p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">Later on it was shown that that Treg depletion via treatment with anti-CD25 mAb (PC61) signiﬁcantly enhances CD8T cell responses to inﬂuenza A virus, vaccinia virus, and SV40-transformed cells induced by either direct priming or cross-priming (<a href="#Haeryfar-SM--DiPaolo-RJ--Tscharke-DC--Bennink-JR--Yewdell-JW--2005-."><span class="Hyperlink">Haeryfar et al., 2005</span></a>). Importantly treatment with PC61 did not enhance CD8T cell responses in the absence of CD4T cells suggesting that PC61 acts on a subset of CD4 T cells, and not on other cells that express CD25. Tregs thus selectively suppress the responses to immuno-dominant CD8 T cell epitopes. </p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">Treg cells generated during an acute infection can influence the magnitude and quality of effector T-cell responses and their ability to contribute to lung pathology during a subsequent heterologous virus infection as is shown for Influenza A virus infection (<a href="#Brincks-EL--Roberts-AD--Cookenham-T--Sell-S--Kohlmeier-JE--Blackman-MA--Woodland-DL--2013-."><span class="Hyperlink">Brincks et al., 2013</span></a>). Accordingly, following challenge with heterosubtypic  IAV infection, antigen-specific IAV-induced Treg cells have been reported to attenuate subsequent T cell responses and decrease pathology during a secondary heterologous IAV challenge (<a href="#Brincks-EL--Roberts-AD--Cookenham-T--Sell-S--Kohlmeier-JE--Blackman-MA--Woodland-DL--2013-."><span class="Hyperlink">Brincks et al., 2013</span></a>).</p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">The presence of Tregs has been convincingly shown to influence viral clearance and immunopathology in the setting of persistent viral infections both in human and animal models (<a href="#Reuter-D--Sparwasser-T--Hunig-T--Schneider-Schaulies-J--2012-."><span class="Hyperlink">Reuter et al., 2012</span></a>; <a href="#Tseng-KC--Ho-YC--Hsieh-YH--Lai-NS--Wen-ZH--Li-C--Wu-SF--2012-"><span class="Hyperlink">Tseng et al., 2012</span></a>). In line with this using a heterologous infection model of persistent and non-persistent viral infections, it was shown for the first time that virus-expanded Treg cells could attenuate immune responses and influence induction of lung pathology during a subsequent unrelated non persistent virus infection (<a href="#Kraft-AR--Wlodarczyk-MF--Kenney-LL--Selin-LK--2013-"><span class="Hyperlink">Kraft et al., 2013</span></a>). </p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">Tregs are usually known to result in a diminished immunopathology as has been shown in autoimmune diseases such as inflammatory bowel or celiac disease (<a href="#Chen-HD--Fraire-AE--Joris-I--Welsh-RM--Selin-LK--2003-."><span class="Hyperlink">Chen et al., 2003</span></a>), and in some viral infections, such as respiratory syncytial virus (RSV) (<a href="#Fulton-RB--Meyerholz-DK--Varga-SM--2010-."><span class="Hyperlink">Fulton et al., 2010</span></a>; <a href="#Ruckwardt-TJ--Bonaparte-KL--Nason-MC--Graham-BS--2009"><span class="Hyperlink">Ruckwardt et al., 2009</span></a>)  and IAV (<a href="#Bedoya-F--Cheng-GS--Leibow-A--Zakhary-2013"><span class="Hyperlink">Bedoya et al., 2013</span></a>; <a href="#Brincks-EL--Roberts-AD--Cookenham-T--Sell-S--Kohlmeier-JE--Blackman-MA--Woodland-DL--2013-."><span class="Hyperlink">Brincks et al., 2013</span></a>). And when these Tregs were depleted by PC61 treatment prior to acute viral infections such as corneal HSV-1, neonatal HSV-1, or i.n. RSV, this results in enhanced immunopathology due to increased virus-specific T-cell responses (<a href="#Fulton-RB--Meyerholz-DK--Varga-SM--2010-."><span class="Hyperlink">Fulton et al., 2010</span></a>; <a href="#Ruckwardt-TJ--Bonaparte-KL--Nason-MC--Graham-BS--2009"><span class="Hyperlink">Ruckwardt et al., 2009</span></a>; <a href="#Suvas-S--Azkur-AK--Kim-BS--Kumaraguru-U--Rouse-BT--2004-"><span class="Hyperlink">Suvas et al., 2004</span></a>). However in contrast to these above mentioned studies, in the heterologous infection model of LCMV and IAV infection, depletion of Treg cells in IAV-immune mice prior to LCMV infection resulted in decreased lung pathology, with no differences in viral titters and significantly decreased LCMV-specific CD8+ T-cell responses in the spleen but not the mLN. </p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">It was then suggested that this was due to the delay in effector T cells trafficking out of the lymph node in the absence of Treg cells in both the LCMV-infected Influenza A virus (IAV)-immune and the naive mice, which is consistent with previous reports demonstrating that Treg cells play a role in controlling egress of effector T cells from the lymph node (<a href="#Lund-JM--Hsing-L--Pham-TT--Rudensky-AY--2008-."><span class="Hyperlink">Lund et al., 2008</span></a>). The important point to note here is that depletion of the IAV-expanded Treg cells during LCMV infection did not significantly enhance virus-specific T-cell responses (<a href="#Haeryfar-SM--DiPaolo-RJ--Tscharke-DC--Bennink-JR--Yewdell-JW--2005-."><span class="Hyperlink">Haeryfar et al., 2005</span></a>; <a href="#Ruckwardt-TJ--Bonaparte-KL--Nason-MC--Graham-BS--2009"><span class="Hyperlink">Ruckwardt et al., 2009</span></a>), which is in contrast to the findings with Treg depletion via PC61 treatment during acute RSV or IAV infection.</p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">Another explanation for the significant reduction in the severity of lung pathology following depletion of Tregs appeared to be mediated by over-activation and subsequent partial exhaustion of the LCMV-specific CD8<span class="CharOverride-2">+</span> T-cell response in LCMV-infected, Treg cell-depleted, IAV-immune mice.</p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">In a mouse model of respiratory viral infection it has been previously shown that influenza (flu)-immune compare to naïve mice infected with Lymphocytic choriomeningitis virus (LCMV) have enhanced viral load, severe lung pathology and an altered cytokine profile. In a study it was found that more CD4<span class="CharOverride-2">+</span>Foxp3<span class="CharOverride-2">+</span> regulatory T (Treg) cells were present in lungs of these flu-immune mice compared to naïve or LCMV-immune mice thus raising the possibility that modulation in the normal balance of Treg and effector T cell responses might be contributing to these altered responses in flu-immune mice infected with LCMV. FLu-immune mice had altered kinetics compared to naïve mice infected with LCMV.</p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">In this heterologous infection model of IAV and LCMV, Treg cells followed the same kinetics as CD4<span class="CharOverride-2">+</span> and CD8<span class="CharOverride-2">+</span> T cells in the mLN of acutely LCMV-infected mice that peaked at day 3 and declined at day 7, in flu-immune mice there was a persistent Treg population at higher levels, until day 9 after LCMV infection. The presence of increased Treg cells in flu-immune lungs and an altered Treg cell kinetics in subsequent heterologous LCMV respiratory infections results in increased viral load and enhanced pro-inflammatory cytokine and chemokine levels in the lungs  and subsequent immunopathology. </p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">Thus, in conclusion, an individual’s history of infection and specific sequence of infection can alter Treg cell populations, resulting in greatly altered disease outcome during subsequent new infections. For a better understanding of the role of Tregs in co-infection systems, our limited literature warrants more detailed studies with various hetrologous infection models in future.</p>
			<p class="Body-Text ParaOverride-1">&nbsp;</p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Heading-1--Introduction----">CONFLICT OF INTEREST</p>
		  <p class="Heading-1--Introduction----">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">Authors declare no conflict of interest.</p>
			<p class="Body-Text ParaOverride-1">&nbsp;</p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
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