4, ACD), consistent with a recent finding that Tfh cells can express both Bcl6 and GATA3 (Zaretsky et al., 2009). during an acute contamination toward T follicular helper cells. Importantly, this sustained CD4 T cell functionality is critical to maintain immunity and ultimately aid in the control of persistent viral contamination. During persistent infection, virus-specific T cells are either actually deleted or persist in an exhausted state, which is usually characterized by the decreased ability to lyse virally infected cells, proliferate, and produce the antiviral and immune stimulatory cytokines IL-2, TNF, and IFN- (Gallimore et al., 1998; Zajac et al., 1998; Wherry et al., 2003; Brooks et al., 2005). It is the culmination of these deficiencies that ultimately prevents viral clearance, leading to persistent contamination. T cell exhaustion is usually observed during many persistent viral infections, including HIV and hepatitis B and hepatitis C computer virus infection in humans and lymphocytic choriomeningitis computer virus (LCMV) contamination in mice, indicating that prolonged viral replication institutes a similar T cell differentiation program (Klenerman and Hill, 2005). Interestingly, persistent LCMV PF-04217903 methanesulfonate infection is usually eventually controlled from the periphery 60C80 d after contamination via CD8 T cellC and B cellCdependent mechanisms, both of which are regulated by CD4 T cells (Battegay et al., 1994; Matloubian et al., 1994; Zajac et al., 1998; RTKN Ciurea et al., 2001; Bergthaler et al., 2009). Consequently, effective CD4 T cell responses are required for the ultimate resolution of persistent LCMV contamination (Battegay et al., 1994; Matloubian et al., 1994). However, it is unclear how exhausted CD4 T cells are able to sustain diverse immune cell types. Depending on the level of TCR stimulation and the composition of co-stimulatory and inflammatory signals, CD4 T cells differentiate into a variety of helper subsets that in turn orchestrate diverse immune responses. We have previously exhibited that priming and initial CD4 T cell activation is similar after acute and persistent LCMV contamination, PF-04217903 methanesulfonate indicating that exhaustion is not a programmed event, but rather a continual response to the antigenic environment (Brooks et al., 2006a), and raising the question as to how differentiation is usually altered during persistent contamination. CD4 T cells continue to help CD8 T cells during persistent viral infection, allowing continued control over computer virus replication (Elsaesser et al., 2009; Fr?hlich et al., 2009; Yi et al., 2009). Although the role of CD8 PF-04217903 methanesulfonate T cells and their differentiation pathways have been extensively analyzed in acute PF-04217903 methanesulfonate and persistent viral contamination (Kaech et al., 2002; Wherry et al., 2007), CD4 T cell differentiation and the mechanisms that govern it are largely uncharacterized. Recently, we as well as others identified IL-21 as a critical component of CD4 T cell help during viral persistence (Elsaesser et al., PF-04217903 methanesulfonate 2009; Fr?hlich et al., 2009; Yi et al., 2009). CD8 T cells require IL-21 to maintain residual levels of immunological function, avoid deletion, and handle persistent infection. IL-21 is also important for stimulating germinal center (GC) B cells and antibody production (Ozaki et al., 2002; Linterman et al., 2010; Zotos et al., 2010), suggesting that CD4 T cells differentiate into a subset capable of providing help to both B cells and CD8 T cells during persistent viral infection. Given that ongoing antiviral immune responses continually exert control over computer virus replication throughout persistent infection and that CD4 T cells play an integral role in this process, we sought to define how viral persistence impacts CD4 T cell differentiation such that it is usually capable of maintaining antiviral immunity in the face of prolonged periods of viral replication. Herein, we establish that the prolonged antigenic stimulation during viral persistence drives a specific CD4 T cell developmental program leading to the progressive differentiation of T follicular helper cells. These CD4 T cells continue to function during viral persistence to sustain antiviral antibody production and to ultimately control persistent virus replication. Thus, we demonstrate that CD4 T cells are not without function during viral persistence, but instead that their developmental program is usually redirected from promoting memory T and B cell differentiation after acute viral contamination and toward a T helper subset that sustains multiple immune parameters to fight persistent viral infection. RESULTS Persistent viral.
4, ACD), consistent with a recent finding that Tfh cells can express both Bcl6 and GATA3 (Zaretsky et al