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-naive, 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. Author Summary Follicular T helper cells (T-FH) interact with B cells within germinal centers of lymphoid tissue to promote the survival, isotype switching and generation of high affinity memory B cells and plasma cells. Recently, a population of circulating CD4 T cells that shares phenotypic and functional characteristics with T-FH cells, named peripheral T-FH cells, has been identified. The relationship between peripheral T-FH cells in the blood and T-FH cells within the lymphoid tissue remains unclear, and whether or not peripheral T-FH cells can provide insight into T cell and B cell dynamics within lymphoid tissue during infection or vaccination is not understood. Here we characterize peripheral T-FH cells and show that unlike T-FH cells, peripheral T-FH cells secrete a diverse array of cytokines and decrease, rather than increase, during chronic HIV infection. Furthermore, we did not observe a relationship between peripheral T-FH cells and memory B cells, or with the production of neutralizing antibodies to HIV. Overall, our data indicate that while peripheral T-FH cells share some characteristics with T-FH cells, they may not represent a good surrogate to study T cell and B cell dynamics within lymphoid tissue.