Reversible Reprogramming of Circulating Memory T Follicular Helper Cell Function during Chronic HIV Infection

Abstract

Despite the overwhelming benefits of antiretroviral therapy (ART) in curtailing viral load in HIV infected individuals, ART does not fully restore cellular and humoral immunity. HIV infected individuals under ART show reduced responses to vaccination and infections and are unable to mount an effective anti-viral immune response upon ART cessation. There are many factors that contribute to these defects including persistent inflammation, especially in lymphoid tissues, where T follicular helper (Tfh) cells instruct and help B cells launch an effective humoral immune response. In this study we investigated the phenotype and function of circulating memory Tfh cells as a surrogate of Tfh cells in lymph nodes and found significant impairment of this cell population in chronically HIV infected individuals leading to reduced B cell responses. We further show that these aberrant memory Tfh cells exhibit an IL-2 responsive gene signature and are more polarized towards a Th1 phenotype. Treatment of functional memory Tfh cells with IL-2 was able to recapitulate the detrimental reprogramming. Importantly, this defect was reversible, as interfering with the IL-2 signaling pathway helped reverse the abnormal differentiation and improved antibody responses. Thus, reversible reprogramming of memory Tfh cells in HIV infected individuals could be utilized to enhance antibody responses. Altered microenvironmental conditions in lymphoid tissues leading to altered Tfh cell differentiation could provide one explanation for the poor responsiveness of HIV infected individuals to new antigens. This has important implications for the development of therapeutic interventions to enhance HIV- and vaccine-mediated antibody responses in patients under ART.

Circulating CXCR5+CXCR3+PD-1lo Tfh-like cells in HIV-1 controllers with neutralizing antibody breadth

“…Unexpectedly, this study showed that the emergence of HIV-1 antibodies with broader neutralizing breadth in HIV-1 controllers was associated with Tfh-like cells expressing CXCR3, a surface marker denoting cells considered less efficient in supporting B cell Ig class switching in previous in vitro studies (15)(16)(17)(18). While our observations confirm that CXCR3 + Tfh-like cells are inferior to CXCR3 -Tfh-like cells in supporting IgG1 class switching, we did demonstrate that CXCR3 + Tfh-like cells have abilities to induce class switching to IgG3 and to alternative Ig subtypes, to secrete high levels of B cell-supporting cytokines, and to induce phenotypical maturation of B cells at equivalent levels as CXCR3 -Tfh-like cells, at least when analyzed over a longer, 6-day co-incubation period with total B cells and SEB stimulation, and not just in a short-term culture assay lasting for 48 hours (15 + Tfh-like cells in maintaining or expanding preexisting B cell responses, but not in the initial priming of new antigen-specific B cells, was also hypothesized in alternative contexts associated with limited antigen exposure, such as in recipients of vaccines against influenza (19).…”

“…The results presented here suggest that a similar developmental hierarchy also exists within the pools of circulating Tfh-like cells, and that PD-1 lo Tfh cells represent a longlived precursor cell population that can replenish the more mature and short-lived PD-1 hi effector Tfh cells. Interestingly, these PD-1 lo Tfh-like cells included a substantial proportion of CD45RO -naive-like T cells, a cell population that was excluded in prior studies (15)(16)(17) but includes a fraction of highly immature memory T cells with increased stem cell-like properties (36). The ability to maintain a larger proportion of PD-1 lo memory Tfh-like cells that are enriched for a T memory stem cell phenotype relative to PD-1 hi pTfh cells could represent a distinct aspect of HIV-1 controllers with more broadly neutralizing antibody responses, and appears to separate these patients from HIV-1 progressors, in whom high-level viremia may lead to more differentiated and possibly more exhausted PD-1 hi pTfh cell populations (52).…”

“…Tfh cells reside in lymphoid tissue (14), but a population of CXCR5 + PD-1 + CD4 + T lymphocytes circulating in the peripheral blood has been proposed to act as peripheral counterparts of Tfh cells (pTfh cells) (15,16 cells express reduced levels of ICOS, Bcl-6, and cellular activation markers such as CD69 and HLA-DR, but maintain the ability to stimulate Ab production and Ig class switching in B cells in vitro upon reactivation with cognate antigens (15,17), suggesting that they represent Tfh-committed memory cells. pTfh cells have been further subdivided into distinct subsets based on expression of CXCR3 and CCR6 receptors, but the contribution of each subtype to the development of humoral immunity remains controversial (16)(17)(18)(19).…”

“…pTfh cells have been further subdivided into distinct subsets based on expression of CXCR3 and CCR6 receptors, but the contribution of each subtype to the development of humoral immunity remains controversial (16)(17)(18)(19). In HIV-1 infection, associations between circulating CXCR5 + CXCR3…”

“…-pTfh cells were able to efficiently induce full class switching to IgG in B cells, dominated by IgG1 ( Figure 4G and Supplemental Figure 6C) (16)(17)(18). In contrast, PD-1 lo and PD-1 hi CXCR3 + cells seemed capable of stimulating B cells to produce IgM, IgA, and IgG3, but not IgG1, as previously reported (16-18), suggesting a more limited ability of these pTfh subsets to support Ig class switching to IgG in our + PD-1 lo (n = 5), CXCR3 + PD-1 hi (n = 5), CXCR3 -PD-1 lo (n = 4), and CXCR3 -PD-1 hi (n = 5).…”