Only a very few HCV-specific CD8+ T cells are required to inhibit HCV replication; inhibition occurs primarily by noncytolytic effector functions.

Background & Aims: Virus-specific CD8 ؉ T cells are required for the control of hepatitis C virus (HCV) infection. We investigated the extent to which different effector functions of CD8 ؉ T cells contribute to the inhibition of viral replication. Methods: We developed a novel immunologic model by stably transducing the HLA-A2 gene into the replicon system, matching the epitope sequence of the replicon to the sequence targeted by an HCV-specific CD8 ؉ T-cell clone. Luciferase activity was then measured to quantitate HCV RNA replication. Results: HCV-specific CD8 ؉ T cells strongly inhibited viral replication, through cytolytic and noncytolytic mechanisms, in a dose-dependent manner. HCV replication was almost completely inhibited at an effector-to-target ratio of 1:1 with significant cytotoxicity; however, >95% viral inhibition occurred at ratios as low as 1:100. Importantly, no cytotoxicity was observed at low effectorto-target ratios, indicating a dominant effect of noncytolytic effector functions that was confirmed by Transwell experiments. Neutralization experiments revealed that interferon gamma mediates the noncytolytic inhibition. Conclusions: Only a very few HCV-specific CD8 ؉ T cells are required to inhibit HCV replication; inhibition occurs primarily by noncytolytic effector functions.

The inhibitory receptor killer cell lectin-like receptor G1 (KLRG1) and the integrin α E (CD103) are expressed by CD8 + T cells and both are specific for E-cadherin. However, KLRG1 ligation by E-cadherin inhibits effector T-cell function, whereas binding of CD103 to E-cadherin enhances cell-cell interaction and promotes target cell lysis. Here, we demonstrate that KLRG1 and CD103 expression in CD8 + T cells from untreated and virus-infected mice are mutually exclusive. Inverse correlation of KLRG1 and CD103 expression was also found in human CD8 + T cells-infiltrating hepatocellular carcinomas. As TGF-β is known to induce CD103 expression in CD8 + T cells, we examined whether this cytokine also regulates KLRG1 expression. Indeed, our data further reveal that TGF-β signaling in mouse as well as in human CD8 + T cells downregulates KLRG1 expression. This finding provides a rationale for the reciprocal expression of KLRG1 and CD103 in different CD8 + T-cell subsets. In addition, it points to the limitation of KLRG1 as a marker for terminally differentiated CD8 + T cells if lymphocytes from tissues expressing high levels of TGF-β are analyzed. Keywords:Killer cell lectin-like receptor G1 r α E (CD103) r E-cadherin. CD8 + T cell r TGF-β Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe killer cell lectin-like receptor G1 (KLRG1) is an E-cadherinspecific inhibitory receptor, which is expressed on different lymphocyte subsets [1][2][3][4]. It is frequently used as a marker for CD8 + T-cell differentiation and in combination with CD127 short-lived effector cells and memory precursor effector cells are discriminated [5]. KLRG1 is expressed in a substantial portion of effector and effector memory CD8 + T cells in blood and secondary lymphoid organs [6]. However, tissue-resident memory CD8 + T (T RM ) cells from various organs such as skin [7], small intestine [8], or Correspondence: Prof. Hanspeter Pircher e-mail: hanspeter.pircher@uniklinik-freiburg.de salivary glands (SG) [9] do not express KLRG1. Similarly, effector memory CD8 + T cells from tumor-infiltrated lymph nodes and tumor tissue show decreased KLRG1 expression compared to cells from the periphery [10,11]. The integrin α E (CD103) represents another receptor for E-cadherin, which is also expressed on subsets of CD8 + T cells [12,13]. In contrast to KLRG1, which inhibits effector cell function [2,4], binding of CD103 to E-cadherin promotes target cell interaction and destruction by cytotoxic CD8 + T cells [14,15]. Thus, KLRG1 and CD103 influence the interaction of CD8 + T cells with their target cells in an opposite manner although they share the same ligand. Here, we demonstrate that KLRG1 and CD103 were reciprocally expressed in mouse as well as in human CD8 + T cells. As TGF-β is known to induce CD103 in CD8 + T cells [13], we further examined whether this cytokine also regulates KLRG1 expression in these cells. Results and discussion Reciprocal expression of KLRG1 and CD103 in mo...

Infection of C57BL/6 mice with lymphocytic choriomeningitis virus (LCMV) strain Armstrong (Arm) induces an acute infection with rapid virus clearance by CD8+ T cells independently of CD4+ T cell help. Residual viral antigen may, however, persist for a prolonged time. Here, we demonstrate that mice that had been transiently depleted of CD4+ T cells during acute LCMV Arm infection generated high levels of virus‐specific IgG antibodies (Ab) after viral clearance. Robust induction of LCMV‐specific IgG after transient CD4+ T cell depletion was dependent on Fcγ receptors but not on the complement receptors CD21/CD35. In contrast to the potent production of LCMV‐specific IgG, the generation of LCMV‐specific isotype‐switched memory B cells after transient CD4+ T cell depletion was considerably reduced. Moreover, mice depleted of CD4+ T cells during acute infection were strongly impaired in generating a secondary LCMV‐specific B cell response upon LCMV rechallenge. In conclusion, our data indicate that LCMV antigen depots after viral clearance were capable of inducing high levels of virus‐specific IgG. They failed, however, to induce robust virus‐specific B cell memory revealing a previously unappreciated dichotomy of specific Ab production and memory cell formation after priming with residual antigen.

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