The PD-1–PD-L1 pathway inhibits perforin-mediated killing of PD-L1+ vascular endothelial cells by CD8+ T cells, thereby limiting vascular damage during systemic LCMV infection.

Persistent viral infections are, by definition, associated with ineffective antiviral immunity, in particular those infections caused by viruses that are highly productive and replicative (including HIV, HBV and HCV). The reasons for ineffective antiviral immunity in these types of infections are complex and manifold, and only recently a more comprehensive picture of the parameters responsible for attenuation of immune function is emerging. One reason for poor viral control in these types of infections is the functional deterioration of antiviral T-cell responses and understanding the underlying mechanisms is of key importance. This review summarizes our current knowledge of cell-intrinsic and cellextrinsic parameters that contribute to T-cell exhaustion during chronic viral infections and discusses related implications for host survival, immunopathology, and control of infection. Key words: Persistent viral infection . T-cell dysfunction . T-cell immunity IntroductionPersistent viral infections, by definition, are not entirely controlled by the host's immune system and are often associated with relevant clinical disease outcomes. Persistent viral infections can be roughly divided into (i) highly productive and replicative infections (associated with continued high abundance of viral antigens) and (ii) latent/reactivating infections (associated with low and perhaps sporadic levels of viral antigens). Well-known examples of the former are HIV, HBV and HCV, which together infect more than 2 billion people worldwide (http://www. unaids.org/; http://www.epidemic.org/; http://www.hepb.org/), and lymphocytic choriomeningitis virus (LCMV) infection in the mouse. Examples of the latter are herpes virus infections, including EBV, CMV, and HSV, which affect together almost 100% of the population. Viruses falling into these two categories have evolved very diverse strategies for co-existence in an immunocompetent host. Highly productive and replicative viruses tend to induce impaired virus-specific adaptive immune responses, which are characterized by limited and dysfunctional T-cell responses, and mutational escape from immune (or drug) pressure are common features of these viruses. Viruses causing latent/reactivating infections have, as a result of their large coding capacity, evolved strategies to interfere with host immunity (immune evasion mechanisms) and have acquired genetic programs that permit a latent, non-replicative existence of the viral genetic information with the option of resuming viral replication in response to certain stimuli. These viral reactivation events, however, are generally well controlled by host immunity and only become clinically apparent in circumstances of immunosuppression.This review focuses on highly productive and replicative persistent viral infections (hereafter referred to as persistent viral infection) with specific emphasis on cell-intrinsic and -extrinsic mechanisms responsible for constraining the size of the antiviral T-cell response and for T-cell dysfunction (summarized in Fig...

Chronic viral infections are often characterized by CD8 T-cell responses with poor cytokine secretion potential and limited expansion of the CD8 T-cell pool, collectively referred to as CD8 T-cell exhaustion. Exhaustion of lymphocytic choriomeningitis virus (LCMV)-specific CD8 T cells was shown to be partially regulated by the inhibitory receptor programmed death 1 (PD-1). Here, we demonstrate that exhausted LCMV-specific CD8 T cells also express the negative regulatory receptor lymphocyte activation gene 3 (LAG-3) which is mainly expressed on cells co-expressing the negative regulatory receptors PD-1 and Tim-3. Expression levels of LAG-3 on anti-viral CD8 T cells remain stable over short-term in vitro stimulations in presence of antigenic peptide. Nevertheless, in vitro and in vivo blockade of LAG-3 did not rescue cytokine production by virus-specific CD8 T cells and did not alter the virus titer in various organs. Likewise, chronic LCMV infection of LAG-3-/- mice led to a comparable degree of T-cell exhaustion as observed in C57BL/6 controls and to similar virus titers. Further, LAG-3 did not influence T-cell activation or cell division during chronic LCMV infection. These data suggest that even though LAG-3 is continuously up-regulated on LCMV-specific exhausted CD8 T cells, it alone does not significantly contribute to T-cell exhaustion.

IL-10 is an anti-inflammatory cytokine that regulates the extent of host immunity to infection by exerting suppressive effects on different cell types. Herpes viruses induce IL-10 to modulate the virus-host balance towards their own benefit, resulting in prolonged virus persistence. To define the cellular and molecular players involved in IL-10 modulation of herpes virus-specific immunity, we studied mouse cytomegalovirus (MCMV) infection. Here we demonstrate that IL-10 specifically curtails the MCMV-specific CD4 T cell response by suppressing the bidirectional crosstalk between NK cells and myeloid dendritic cells (DCs). In absence of IL-10, NK cells licensed DCs to effectively prime MCMV-specific CD4 T cells and we defined the pro-inflammatory cytokines IL-12, IFN-γ and TNF-α as well as NK cell activating receptors NKG2D and NCR-1 to regulate this bidirectional NK/DC interplay. Consequently, markedly enhanced priming of MCMV-specific CD4 T cells in Il10 −/− mice led to faster control of lytic viral replication, but this came at the expense of TNF-α mediated immunopathology. Taken together, our data show that early induction of IL-10 during MCMV infection critically regulates the strength of the innate-adaptive immune cell crosstalk, thereby impacting beneficially on the ensuing virus-host balance for both the virus and the host.

One Sentence SummaryWe demonstrate that continued presence of CXCR5 +/+ TFH cells throughout chronic viral infection is dispensable for maintenance of overall virus-specific antibody titers but is vital for the generation of virus-neutralizing antibodies and eventual control of the infection.