Negative Co-stimulation Constrains T Cell Differentiation by Imposing Boundaries on Possible Cell States

Abstract

Graphical AbstractHighlights d Negative co-stimulation limits T cell differentiation outcomes d Archetypal analysis identifies phenotypic boundaries of cell states d CTLA-4 imposes major boundaries on CD4 + T cell phenotypes d PD-1 subtly restrains CD8 + T cell phenotypes Negative co-stimulation is a critical regulator of T cell activity. Wei et al. characterize T cells arising in CTLA-4and PD-1-deficient mice via masscytometry and computational approaches. They show that these negative co-stimulatory molecules impose boundaries on T cell phenotypes during peripheral differentiation, suggesting that checkpoint blockade might work in part by altering the limits of T cell phenotypes. SUMMARYCo-stimulation regulates T cell activation, but it remains unclear whether co-stimulatory pathways also control T cell differentiation. We used mass cytometry to profile T cells generated in the genetic absence of the negative co-stimulatory molecules CTLA-4 and PD-1. Our data indicate that negative co-stimulation constrains the possible cell states that peripheral T cells can acquire. CTLA-4 imposes major boundaries on CD4 + T cell phenotypes, whereas PD-1 subtly limits CD8 + T cell phenotypes. By computationally reconstructing T cell differentiation paths, we identified protein expression changes that underlied the abnormal phenotypic expansion and pinpointed when lineage choice events occurred during differentiation. Similar alterations in T cell phenotypes were observed after anti-CTLA-4 and anti-PD-1 antibody blockade. These findings implicate negative co-stimulation as a key regulator and determinant of T cell differentiation and suggest that checkpoint blockade might work in part by altering the limits of T cell phenotypes.

mTOR and other effector kinase signals that impact T cell function and activity

“…Lastly, studies have also implicated the possibility for CTLA‐4 negative co‐stimulation in the regulation of tonic signals. Knockout of CTLA‐4 in mice leads to aberrant T cell differentiation, indicated by the presence of non‐canonical CD4 + T helper cell subtypes only in the knockout mice . Intriguingly, data from this study illustrate the possibility that CTLA‐4 restricts tonic signaling by raising the threshold for differentiation of promiscuous clones.…”

“…Intriguingly, data from this study illustrate the possibility that CTLA‐4 restricts tonic signaling by raising the threshold for differentiation of promiscuous clones. T cells from CTLA‐4 deficient mice may be more responsive to self‐antigens as well, as CTLA‐4 deletion was correlated with decreased N region insertions, which can contribute to self‐reactivity . How exactly CTLA‐4 may receive or transduce tonic signals remains to be defined, but these recent data provide an important starting point.…”

Single residue in CD28-costimulated CAR-T cells limits long-term persistence and antitumor durability

“…Th17 cells display a molecular signature consistent with stem-like properties, can give rise to Th1-like cells while also self-renewing to maintain a population of IL-17A-secreting cells, and demonstrate increased antitumor potency over Th1 cells when adoptively transferred in mouse models of melanoma (66,67). In the absence of negative costimulation by CTLA4 or after anti-CTLA4 antibody blockade, CD4 + T cells can differentiate into an ICOS + Th1-skewed population with superphysiological cytokine output capabilities (68). On a molecular level, these results suggest that the ICOS YMFM motif is at least in part responsible for CD4 + T cell differentiation toward a Th17 phenotype.…”

Generation of highly activated, antigen-specific tumor-infiltrating CD8 + T cells induced by a novel T cell-targeted immunotherapy

“…Another study 42 suggests the survival of subdominant CD8 + T cell clones is usually negatively affected by immunodominant clones; however, PD-1 blockade inhibits this effect thus enhancing survival and population size. In another study, 43 CTLA-4 knockout mice had increased T cell clonality in the lymph node, while Karandikar et al 44 showed that CTLA-4 blockade during the acute phase of experimental autoimmune encephalomyelitis leads to enhanced epitope spreading. Both of these studies suggest that the T cell clonality mechanism was due to CTLA-4 being a natural inhibitor of self-reactive or subdominant clones and that blocking CTLA-4 lowers the threshold for activation of both clonotypes.…”