Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy

Abstract

Chronic viral infections are characterized by a state of CD8+ T-cell dysfunction that is associated with expression of the programmed cell death 1 (PD-1) inhibitory receptor1–4. A better understanding of the mechanisms that regulate CD8+ T cell responses during chronic infection is required to improve immunotherapies that restore function in exhausted CD8+ T cells. Here we identify a population of virus-specific CD8+ T cells that proliferate after blockade of the PD-1 inhibitory pathway in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). These LCMV-specific CD8+ T cells expressed the PD-1 inhibitory receptor but also expressed several costimulatory molecules such as ICOS and CD28. This CD8+ T cell subset was characterized by a unique gene signature that was related to that of CD4+ T follicular helper (TFH) cells, CD8+ T cell memory precursors and haematopoietic stem cell progenitors, but that was distinct from that of CD4+ TH1 cells and CD8+ terminal effectors. This CD8+ T cell population was found only in lymphoid tissues and resided predominantly in the T cell zones along with naïve CD8+ T cells. These PD-1+ CD8+ T cells resembled stem cells during chronic LCMV infection, undergoing self-renewal and also differentiating into the terminally exhausted CD8+ T cells that were present in both lymphoid and non-lymphoid tissues. The proliferative burst after PD-1 blockade came almost exclusively from this CD8+ T cell subset. Notably, the transcription factor TCF1 had a cell intrinsic and essential role in the generation of this CD8+ T cell subset. These findings provide a better understanding of T cell exhaustion and have implications in the optimization of PD-1-directed immunotherapy in chronic infections and cancer.

Antigen-specificity and DTIC before peptide-vaccination differently shape immune-checkpoint expression pattern, anti-tumor functionality and TCR repertoire in melanoma patients

“…In particular, T cells isolated from patients treated with vaccination alone showed a less differentiated phenotype in terms of CD28 expression (Arm1, mean ± SD 56% ± 27%), as compared with cells isolated from patients treated with chemo-immunotherapy (Arm2, mean ± SD 6% ± 10%; P < 0.0001). The intermediate differentiated profile of gp100 + T-cell clonotypes derived from vaccination alone was also supported by the expression analysis of C-X-C chemokine receptor type 5 (CXCR5), a marker recently associated with memory stem cell-like CD8 + T cells, 26 , 27 significantly higher in Arm1 (mean ± SD 43% ± 6.9%) as compared with Arm2 (mean ± SD 34% ± 3.3%, P = 0.03), either alone (Table 1) or in co-expression with CD28 ( P = 0.006, data not shown). The analysis of the expression of CD56 and Natural Killer Group 2D (NKG2D), markers for activation and effector functionality, revealed no difference for CD56 but a heterogeneous expression for NKG2D (Table 1).…”

“…This early differentiated effector memory CD8 + CD28 high PD1 + CXCR5 + subgroup has recently been reported as the only proliferative subset after anti-PD-1 blockade in mice chronically infected with a Lymphocytic Choriomeningitis Virus. 26 , 27 Since these T cells are not functional in our model, further studies are needed to understand whether anti-PD1 treatment may be beneficial in patients possessing a substantial frequency of this T-cell subset. Differently, combined immunotherapy expanded anti-tumor functional CD8 + T cell with low levels of CD28 and PD-1.…”

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

“…GC Tfh cells are not only highly activated cells that are good targets for HIV‐1 infection but are also located in close proximity to FDCs, which are an important reservoir of infectious virus and can readily transmit infection to Tfh cells 180, 181, 182, 183. Virus replication in GC Tfh cells may also be facilitated by the limited ability of antiviral CD8 + T cells to enter B‐cell follicles,168, 171, 175, 179, 184 although recent studies in the lymphocytic choriomeningitis virus (LCMV) mouse model show that persisting virus can be cleared from Tfh cells and B cells by a CXCR5 +  CD8 + T‐cell population that is able to enter B‐cell follicles,185, 186, 187 raising the intriguing prospect that if an analogous antiviral CD8 + T‐cell population expressing sufficiently high levels of CXCR5 could be induced in humans, this may enable targeting of Tfh cells that harbor persistent HIV‐1 such as the latent pool.…”

Physiology and Pathology of Immune Dysregulation: Regulatory T Cells and Anergy

“…T cells do not exhaust uniformly during chronic diseases or cancer, but instead specific subsets with different memory and proliferative potentials emerge after exposure to persistent antigen [122,123].…”