The ability for a single T cell to upregulate multiple effector functions, polyfunctionality, is crucial for protective immunity. Loss of polyfunctional T cells during chronic viral infections is associated with pathogen persistence and results in poor memory T cell formation and progressive T cell exhaustion. However, the molecular mechanisms determining the generation and maintenance of polyfunctional T cells remain unclear. We found that CD8+ T cell polyfunctionality can be directly regulated by antigen dose. High antigen dose stimulation induced robust T cell proliferation but, in contrast, only poorly polyfunctional T cells. Microarray analysis revealed that poorly polyfunctional T cells induced by high dose antigen had a unique transcription profile similar to exhausted T cells observed during chronic viral infections including upregulation of inhibitory receptors. However, the poorly polyfunctional T cell state was independent of inhibitory receptor signaling. Instead, biochemical and genetic experiments showed that the inhibition of MAPK/ERK pathway through upregulation of spry2, a negative regulator of the MAPK/ERK pathway, directly modulated polyfunctionality by selectively inhibiting cytokine secretion. Our findings reveal novel mechanisms controlling human T cell polyfunctionality and are directly relevant to effective vaccine development and T cell immunotherapy.
- Copyright © 2013 by The American Association of Immunologists, Inc.