Abstract
The intrahepatic immune environment is normally biased towards tolerance. Nonetheless, effective antiviral immune responses can be induced against hepatotropic pathogens. To examine the immunological basis of this paradox we studied the ability of hepatocellularly expressed hepatitis B virus (HBV) to activate immunologically naïve HBV-specific CD8+ T cell receptor (TCR) transgenic T cells after adoptive transfer to HBV transgenic mice. Intrahepatic priming triggered vigorous in situ T cell proliferation but failed to induce interferon gamma production or cytolytic effector function. In contrast, the same T cells differentiated into cytolytic effector T cells in HBV transgenic mice if Programmed Death 1 (PD-1) expression was genetically ablated, suggesting that intrahepatic antigen presentation per se triggers negative regulatory signals that prevent the functional differentiation of naïve CD8+ T cells. Surprisingly, coadministration of an agonistic anti-CD40 antibody (αCD40) inhibited PD-1 induction and restored T cell effector function, thereby inhibiting viral gene expression and causing a necroinflammatory liver disease. Importantly, the depletion of myeloid dendritic cells (mDCs) strongly diminished the αCD40 mediated functional differentiation of HBV-specific CD8+ T cells, suggesting that activation of mDCs was responsible for the functional differentiation of HBV-specific CD8+ T cells in αCD40 treated animals. These results demonstrate that antigen-specific, PD-1-mediated CD8+ T cell exhaustion can be rescued by CD40-mediated mDC-activation.
Highlights
Rapid clonal expansion of CD8+ T cells in response to antigenic challenge is a hallmark of adaptive immunity and a crucial element of host defense
We find that these T cells are primed in the liver when they are adoptively transferred into hepatitis B virus (HBV) transgenic mouse recipients whose livers produce infectious virus particles, and that they proliferate vigorously in situ but do not differentiate into functional effector T cells after antigen recognition
By analyzing the response of naıve CORand ENV-specific T cell receptor (TCR) transgenic CD8+ T cells to hepatocellularly presented HBV antigens in vivo after adoptive transfer into HBV transgenic mice whose hepatocytes produce all the HBV gene products and secrete infectious HBV virions [19], and in vitro after cocultivation with primary HBV transgenic mouse hepatocytes, we show that HBV-specific naıve CD8+ T cells are primed in the liver by HBV+ hepatocytes and proliferate vigorously in situ, but do not differentiate into functional effector T cells unless Programmed Death 1 (PD-1) signaling is genetically ablated
Summary
Rapid clonal expansion of CD8+ T cells in response to antigenic challenge is a hallmark of adaptive immunity and a crucial element of host defense. Activation and differentiation of T cells are largely determined by their initial encounter with antigenpresenting cells (APCs), and the resultant responses range from full activation and memory T cell differentiation to clonal exhaustion or deletion, depending on the nature and abundance of inductive signals that T cells decode from APCs during priming [1,2]. These events generally occur in secondary lymphoid organs because naıve T cells are usually not primed in nonlymphoid tissues [2]. Because of its unique immunological environment, antigens expressed and/or processed in the liver appear to be more accessible to T cells than those in other nonlymphoid organs [4,15]
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