The role of CD4+ T cells in the control of infectious pathogens is highly complex with a myriad of functions but how these T cells acquire differential functional potentiality remains poorly defined. Here we show that human cytomegalovirus (CMV)-specific CD4+ T cells directed towards different viral antigens expressed predominantly TNF-α alone or TNF-α and IFN-γ. TNF-α+ and IFN-γ+ CD4+ T cells expressed significantly higher levels of T-box transcription factors T-bet with graded loss of Eomesodermin (Eomes) expression (T-betHi EomesHi/Lo) when compared with TNF-α+ CD4+ T cells expressing lower levels of both T-bet and Eomes (T-bet- Eomes-). Furthermore, TNF-α+ and IFN-γ+ CD4+ T cells expressed significantly higher levels of perforin and interleukin (IL)-2 and displayed a terminally differentiated phenotype (CCR7- CD27 - CD45RA- CD57+ CD62L-). In contrast, TNF-α+ alone CMV-specific CD4+ T cells were predominantly early-memory phenotype with a proportion of these cells displaying T memory stem-cell phenotype (CD95+ CD45RA+ CCR7+ CD27+). In vitro stimulation of CMV-specific CD4+ T cells with viral antigen in the presence of IL-12 was sufficient to dramatically change the transcriptional and functional profile of TNF-α+ CD4+ T cells, whereas TNF-α+ and IFN-γ+ CD4+ T cells remained unaltered. These findings illustrate an intrinsic link between cytokine expression, transcriptional regulation and cellular differentiation, and their impact on functional plasticity of virus-specific CD4+ T cells.
- T cells
- Transcription factors