Loss of Circulating CD4 T Cells with B Cell Helper Function during Chronic HIV Infection

The interaction between follicular T helper cells (T(FH)) and B cells in the lymph nodes and spleen has a major impact on the development of antigen-specific B cell responses during infection or vaccination. Recent studies described a functional equivalent of these cells among circulating CD4 T cells, referred to as peripheral T(FH) cells. Here, we characterize the phenotype and in vitro B cell helper activity of peripheral T(FH) populations, as well as the effect of HIV infection on these populations. In co-culture experiments we confirmed CXCR5+ cells from HIV-uninfected donors provide help to B cells and more specifically, we identified a CCR7(high)CXCR5(high)CCR6(high)PD-1(high) CD4 T cell population that secretes IL-21 and enhances isotype-switched immunoglobulin production. This population is significantly decreased in treatment-naïve, HIV-infected individuals and can be recovered after anti-retroviral therapy. We found impaired immunoglobulin production in co-cultures from HIV-infected individuals and found no correlation between the frequency of peripheral T(FH) cells and memory B cells, or with neutralization activity in untreated HIV infection in our cohort. Furthermore, we found that within the peripheral T(FH) population, the expression level of T(FH)-associated genes more closely resembles a memory, non-T(FH) population, as opposed to a T(FH) population. Overall, our data identify a heterogeneous population of circulating CD4 T cells that provides in vitro help to B cells, and challenges the origin of these cells as memory T(FH) cells.