Role of PD-1 during effector CD8 T cell differentiation

Abstract

PD-1 (programmed cell death-1) is the central inhibitory receptor regulating CD8 T cell exhaustion during chronic viral infection and cancer. Interestingly, PD-1 is also expressed transiently by activated CD8 T cells during acute viral infection, but the role of PD-1 in modulating T cell effector differentiation and function is not well defined. To address this question, we examined the expression kinetics and role of PD-1 during acute lymphocytic choriomeningitis virus (LCMV) infection of mice. PD-1 was rapidly up-regulated in vivo upon activation of naive virus-specific CD8 T cells within 24 h after LCMV infection and in less than 4 h after peptide injection, well before any cell division had occurred. This rapid PD-1 expression by CD8 T cells was driven predominantly by antigen receptor signaling since infection with a LCMV strain with a mutation in the CD8 T cell epitope did not result in the increase of PD-1 on antigen-specific CD8 T cells. Blockade of the PD-1 pathway using anti-PD-L1 or anti-PD-1 antibodies during the early phase of acute LCMV infection increased mTOR signaling and granzyme B expression in virus-specific CD8 T cells and resulted in faster clearance of the infection. These results show that PD-1 plays an inhibitory role during the naive-to-effector CD8 T cell transition and that the PD-1 pathway can also be modulated at this stage of T cell differentiation. These findings have implications for developing therapeutic vaccination strategies in combination with PD-1 blockade.

Lentiviral Vector-Based Dendritic Cell Vaccine Suppresses HIV Replication in Humanized Mice

“…It has been shown that PD-1 is induced early in T cell activation, inhibiting the differentiation of effector CD8 T cells. 63 The PD-1 microbody might prevent early induction of PD-1, accounting for the more rapid response in humanized mice. Compared with humanized mice vaccinated with HIV.GFP-transduced DCs that express HIV-1 antigens but lack the PD-1 microbody and CD40L, HIV.PD1-CD40L-transduced DCs accelerated virus suppression and induced more functional HIV-specific T cells, although this was a modest effect.…”

Cancer Vaccines: Steering T Cells Down the Right Path to Eradicate Tumors

“…Although anti-PD-1 or anti-PD-L1 antibodies are an obvious combination partner for a cancer vaccine, recent preclinical data suggest that optimal sequencing of these therapies may be critical for achieving maximal antitumor activity. In the lymphocytic choriomeningitis virus (LCMV) model, abrogation of the PD-1 pathway led to impaired formation of LCMV-specific memory T cells while the addition of PD-1 inhibition to a regimen of combined OX-40 agonistic and a peptide vaccine in the human papillomavirus-associated tumor model TC-1 compromised efficacy and led to apoptosis of tumor-infiltrating vaccine-specific T cells (43,44). These data indicate that a cancer vaccine may be most effective if administered prior to initiation of PD-1 pathway inhibition.…”

B cell Compartmentalization in Blood and Cerebrospinal Fluid of HIV-Infected Ugandans with Cryptococcal Meningitis

“…Whether ectopic germinal centers are 290 present in the brain with cryptococcal meningitis, which has a prominent component in 291 the brain parenchyma, as were identified with neurosyphilis (40) was increased on activated B cells, particularly CD27+ and tissue-like memory cells, as 307 reported by others (43,45). Indeed, microbial antigens, modeled by toll-like receptor-9 to its effects on T cells, PD-1 on B cells can inhibit B cell activation, suppress B cell 310 proliferation and impair B cell inflammatory cytokine responses (12,13,45,47). 311…”