Key Points• Number of prior chemotherapy cycles in cancer patients correlates with T-cell senescent phenotype and loss of CD27 and CD28 expression.• Addition of PI3Kd inhibitors and VIP antagonists increased ex vivo expansion, in vivo persistence, and anticancer cytotoxicity of T cells.

Effector CD8 + T cells are important mediators of adaptive immunity, and receptor-ligand interactions that regulate their survival may have therapeutic potential. Here, we identified a subset of effector CD8 + T cells that expressed the inhibitory fragment crystallizable (Fc) receptor FcgRIIB following activation and multiple rounds of division. CD8 + T cell-intrinsic genetic deletion of Fcgr2b increased CD8 + effector T cell accumulation, resulting in accelerated graft rejection and decreased tumor volume in mouse models. Immunoglobulin G (IgG) antibody was not required for FcgRIIB-mediated control of CD8 + T cell immunity, and instead, the immunosuppressive cytokine fibrinogen-like 2 (Fgl2) was a functional ligand for FcgRIIB on CD8 + T cells. Fgl2 induced caspase-3/7-mediated apoptosis in Fcgr2b + , but not Fcgr2b À/À , CD8 + T cells. Increased expression of FcgRIIB correlated with freedom from rejection following withdrawal from immunosuppression in a clinical trial of kidney transplant recipients. Together, these findings demonstrate a cell-intrinsic coinhibitory function of FcgRIIB in regulating CD8 + T cell immunity.

SHP1 is a tyrosine phosphatase critical to proximal regulation of TCR signaling. Here, analysis of CD4-Cre SHP1fl/fl conditional knockout thymocytes using CD53, TCRβ, CD69, CD4 and CD8α expression demonstrates the importance of SHP1 in the survival of post selection (CD53+), single-positive thymocytes. Using Ca2+ flux to assess the intensity of TCR signaling demonstrated that SHP1 dampens the signal strength of these same mature, post-selection thymocytes. Consistent with its dampening effect, TCR signal strength was also probed functionally using peptides that can mediate selection of the OT-I TCR, to reveal increased negative selection mediated by lower-affinity ligand in the absence of SHP1. Our data show that SHP1 is required for the survival of mature thymocytes and the generation of the functional T-cell repertoire, as its absence leads to a reduction in the numbers of CD4+ and CD8+ naïve T cells in the peripheral lymphoid compartments.

The virtual crossmatch (VXM) is gaining acceptance as an alternative approach to assess donor:recipient compatibility prior to transplantation. In contrast to a physical crossmatch, the virtual crossmatch does not require viable donor cells but rather relies on complete HLA typing of the donor and current antibody assessment of the recipient. Thus, the VXM can be performed in minutes which allows for faster transplant decisions thereby increasing the likelihood that organs can be shipped across significant distances yet safely transplanted. Here, we present a brief review of the past 50 years of histocompatibility testing; from the original complement‐dependent cytotoxicity crossmatch in 1969 to the new era of molecular HLA typing, solid‐phase antibody testing and virtual crossmatching. These advancements have shaped a paradigm shift in our approach to transplantation. That is, foregoing a prospective physical crossmatch in favor of a VXM. In this review, we undertake an in‐depth analysis of the pros‐ and cons‐ of physical and virtual crossmatching.Finally, we provide objective data on the selected use of the VXM which demonstrate the value of a VXM in lieu of the traditional physical crossmatch for safe and efficient organ transplantation.

In the setting of cancer, T cells upregulate coinhibitory molecules that attenuate TCR signaling and lead to the loss of proliferative capacity and effector function. Checkpoint inhibitors currently in clinical use have dramatically improved mortality from melanoma yet are not effective in all patients, suggesting that additional pathways may contribute to suppression of tumor-specific CD8 + T cell responses in melanoma. Here, we show that FcγRIIB, an inhibitory Fc receptor previously thought to be exclusively expressed on B cells and innate immune cells, is upregulated on tumor-infiltrating effector CD8 + T cells in an experimental melanoma model and expressed on CD8 + T cells in patients with melanoma. Genetic deficiency of Fcgr2b resulted in enhanced tumor-infiltrating CD8 + T cell responses and significantly reduced tumor burden. Adoptive transfer experiments of Fcgr2b –/– tumor antigen-specific T cells into FcγRIIB-sufficient hosts resulted in an increased frequency of tumor-infiltrating CD8 + T cells with greater effector function. Finally, FcγRIIB was expressed on CD8 + memory T cells isolated from patients with melanoma. These data illuminate a cell-intrinsic role for the FcγRIIB checkpoint in suppressing tumor-infiltrating CD8 + T cells.