Date Published: December 7, 2015
Publisher: Public Library of Science
Author(s): Félicien Moukambi, Henintsoa Rabezanahary, Vasco Rodrigues, Gina Racine, Lynda Robitaille, Bernard Krust, Guadalupe Andreani, Calayselvy Soundaramourty, Ricardo Silvestre, Mireille Laforge, Jérôme Estaquier, Guido Silvestri.
Follicular T helper cells (Tfh), a subset of CD4 T lymphocytes, provide crucial help to B cells in the production of antigen-specific antibodies. Although several studies have analyzed the dynamics of Tfh cells in peripheral blood and lymph nodes (LNs) during Aids, none has yet addressed the impact of SIV infection on the dynamics of Tfh cells in the spleen, the primary organ of B cell activation. We show here a significant decrease in splenic Tfh cells in SIVmac251-infected rhesus macaques (RMs) during the acute phase of infection, which persists thereafter. This profound loss is associated with lack of sustained expression of the Tfh-defining transcription factors, Bcl-6 and c-Maf but with higher expression of the repressors KLF2 and Foxo1. In this context of Tfh abortive differentiation and loss, we found decreased percentages of memory B cell subsets and lower titers of SIV-specific IgG. We further demonstrate a drastic remodeling of the lymphoid architecture of the spleen and LNs, which disrupts the crucial cell-cell interactions necessary to maintain memory B cells and Tfh cells. Finally, our data demonstrated the early infection of Tfh cells. Paradoxically, the frequencies of SIV DNA were higher in splenic Tfh cells of RMs progressing more slowly suggesting sanctuaries for SIV in the spleen. Our findings provide important information regarding the impact of HIV/SIV infection on Tfh cells, and provide new clues for future vaccine strategies.
The follicular T helper (Tfh) cell, part of the T helper cell populations, tightly controls germinal center (GC) development. Tfh are considered to be a distinct CD4 T cell type with great importance for protective immunity. Rare in the blood, Tfh are essential for maintaining GCs and mediate B cell affinity maturation [1,2]. Tfh provide survival and proliferation signals to B cells via multiple pathways, including CD40L, IL-21, and BAFF, which compete with Fas-FasL interactions [3–5]. IL-21 production by Tfh has an important function, as B cells are usually aberrant in the absence of IL-21 [4–6]. Moreover, IL-21 is a critical factor for the control of chronic viral infections [7–9]. Tfh cells selectively express CXCR5 and PD-1 [10,11] but only weakly CCR5, CCR2, CX3CR1, and related inflammatory cytokine receptors . BCL6 and MAF have been identified as master regulators of their differentiation [12–16].
Our results revealed that splenic Tfh cells, which are expressing IL-21 mRNA, are specifically depleted early after SIV-infection in RMs. Moreover, we found an increase of the inhibitory transcriptional factors KLF2 and Foxo1 as well as an absence of sustained expression of Bcl-6 and c-Maf, which are essential for Tfh differentiation. This abortive differentiation of Tfh cells concomitantly with the alteration of the architecture of the spleen impaired their interaction with B cells leading to the loss of memory B cells, and the production of SIV antibodies. Thus, our data suggests that depletion of splenic Tfh cells in individuals may represent a critical component in HIV immunodeficiency given that the spleen represents the main organ for the initiation of B cell responses.