Antigen-dependent clonal expansion of a trace population of antigen-specific CD4+ T cells in vivo is dependent on CD28 costimulation and inhibited by CTLA-4.

Abstract

The importance of CD28 costimulation to a primary T cell response in vivo was assessed in an adoptive transfer system where a small population of peptide-specific CD4+ TCR transgenic T cells can be physically tracked. Ag-dependent clonal expansion of the transgenic T cells in draining lymph nodes was blocked by cyclosporin A and required a CD28 signal that was completely inhibited by CTLA-4-Ig or a combination of anti-B7-1 and anti-B7-2 mAbs, but not by either Ab alone. In vivo treatment with the combination of anti-B7-1 and anti-B7-2 mAbs also blocked conversion of the Ag-specific T cells to the activated phenotype. In contrast, anti-CTLA-4 Fab greatly enhanced the in vivo clonal expansion of the Ag-specific T cells. These results suggest that Ag-driven proliferation and phenotype conversion of naive CD4+ T cells is dependent on CD28-derived signals and is inhibited by CTLA-4.

Lung tumor-infiltrating Treghave divergent transcriptional profiles and function linked to checkpoint blockade response

“…S7g ). This frequency of SMARTA TCR+ T reg in the tumor after one day is consistent with prior studies of adoptively-transferred CD4+ T cells ( 36 ).…”

“…Of note, fewer than 1% of total T reg in the spleen were from the donor SMARTA TCR pos T reg 14 days after adoptive transfer, a proportion similar to previous protocols using adoptively transferred T conv ( Fig. S6c )( 36 ).…”

Lung tumor–infiltrating T reg have divergent transcriptional profiles and function linked to checkpoint blockade response

“…Notably, fewer than 1% of total T reg in the spleen were from the donor SMARTA TCR + T reg 14 days after adoptive transfer, a proportion similar to previous protocols using adoptively transferred T conv (fig. S6D) ( 53 ).…”

Supplementary Methods from Bevacizumab plus Ipilimumab in Patients with Metastatic Melanoma

“…Although there was initially some controversy as to the role of CTLA-4 in regulating T cell activation, it has become clear that CTLA-4 down-regulates T cell responses (21). This was initially suggested by the following in vitro observations: (1) blockade of CTLA-4/B7 interactions with antibody enhanced T cell responses; (2) cross-linking of CTLA-4 with CD3 and CD28 inhibited T cell responses; and (3) administration of antibodies to CTLA-4 in vivo enhanced the immune response to peptide antigens or superantigens in mice (22)(23)(24)(25). Blocking CTLA-4-B7 interaction while preserving signaling via CD28 resulted in enhanced T cell responses in vitro.…”