We have investigated the phenotype, function, location and molecular signature of follicular CD4 T helper cells (TFH) in rhesus macaques. Similar to human TFH, they are characterized by a CCR7lowPD-1highCTLA-4highICOShighCXCR4high phenotype and represent a heterogeneous population with respect to cytokine function. Production of Th1 cytokines was compromised while IL-4 production was augmented in a highly differentiated (CD150low) subpopulation of TFH cells that was also characterized by decreased survival, cycling, and trafficking capacity. Compared to non-TFH cells, TFH cells exhibited a distinct gene profile that was significantly altered by SIV infection. TFH cells were found to be infected by SIV yet, in some animals, these cells actually accumulated during chronic SIV infection. Generalized immune activation and increased IL-6 production helped drive TFH differentiation during SIV infection. Accumulation of TFH was associated with increased frequency of activated germinal center B cells and SIV-specific antibodies. These processes contribute to B cell and immunoglobulin abnormalities in SIV, and by extension HIV, infection.
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