Sprouty-2 regulates HIV-specific T cell polyfunctionality

Abstract

The ability of individual T cells to perform multiple effector functions is crucial for protective immunity against viruses and cancer. This polyfunctionality is frequently lost during chronic infections; however, the molecular mechanisms driving T cell polyfunctionality are poorly understood. We found that human T cells stimulated by a high concentration of antigen lacked polyfunctionality and expressed a transcription profile similar to that of exhausted T cells. One specific pathway implicated by the transcription profile in control of T cell polyfunctionality was the MAPK/ERK pathway. This pathway was altered in response to different antigen concentrations, and polyfunctionality correlated with upregulation of phosphorylated ERK. T cells that were stimulated with a high concentration of antigen upregulated sprouty-2 (SPRY2), a negative regulator of the MAPK/ERK pathway. The clinical relevance of SPRY2 was confirmed by examining SPRY2 expression in HIV-specific T cells, where high levels of SPRY2 were seen in HIV-specific T cells and inhibition of SPRY2 expression enhanced the HIV-specific polyfunctional response independently of the PD-1 pathway. Our findings indicate that increased SPRY2 expression during chronic viral infection reduces T cell polyfunctionality and identify SPRY2 as a potential target for immunotherapy.

Aberrant Expression of MHC Class II in Melanoma Attracts Inflammatory Tumor-Specific CD4+ T- Cells, Which Dampen CD8+ T-cell Antitumor Reactivity

“…It is anyway difficult to draw firm conclusions, because most T-cell recognition analyses in Linnemann and colleagues (11) were performed with autologous B cells (presenting neoantigens) as targets and not tumor cells. It is indeed known from previous studies that several factors can affect T-cell functionality, including antigen density (38,39) that may of course be different in peptide-loaded APCs and tumor cells. Future studies will determine whether functional differences exist between CD4 þ T-cell subsets specific to different classes of tumor antigens.…”

Phenotypic models of T cell activation

“…c | Experiments using detailed antigen titration have also shown that the dissociation time determines both the potency (EC 50 ) and maximal efficacy (E max ), such that antigens with short dissociation times cannot produce the same maximal response as antigens with long dissociation times 6,13 . Recent data have also suggested the existence of an optimal antigen dose for T cell activation (not shown) 39,40 . Note that panels b and c are schematics.…”

“…3). There is some experimental evidence for an optimal antigen dose 24, 39,40 , but additional work with antigens of varying affinities is needed. (FIG.…”

The Transcription Factor NFAT1 Participates in the Induction of CD4+T Cell Functional Exhaustion during Plasmodium yoelii Infection

“…At least two mediators of TCR signals, SPRY2 and NFAT, have been identified as factors involved in supporting the establishment of exhaustion in CD8 ϩ T cells (25,26). Our data indicate that NFAT1 is also a central regulator of the induction of exhaustion in CD4 ϩ T cells.…”