Early Loss of Splenic Tfh Cells in SIV-Infected Rhesus Macaques.

Félicien Moukambi,Jérôme Estaquier,Calayselvy Soundaramourty,Henintsoa Rabezanahary,Guadalupe Andreani,Lynda Robitaille,Vasco Rodrigues,Bernard Krust,Mireille Laforge,Ricardo Silvestre,Gina Racine

doi:10.1371/journal.ppat.1005287

Abstract

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.

Highlights

The follicular T helper (Tfh) cell, part of the T helper cell populations, tightly controls germinal center (GC) development
Because we recently reported the transient expansion of a population of CXCR5+ Tfh-like cells that fail to express PD-1 during L. infantum infection of rhesus macaques (RMs) [28], we analyzed more in detail the dynamics of CD4 T cells expressing CXCR5 and PD-1 during SIV infection (Fig 3A)
Consistent with previous reports [52,53,54,55,56,57], we found in peripheral blood lower percentages of resting and activated memory B cells (Fig 5B, left panel) in SIV-infected RMs compared to the percentages before infection

Summary

Introduction

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. 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 [3,4,5]. IL-21 production by Tfh has an important function, as B cells are usually aberrant in the absence of IL-21 [4,5,6]. Tfh cells selectively express CXCR5 and PD-1 [10,11] but only weakly CCR5, CCR2, CX3CR1, and related inflammatory cytokine receptors [12]. BCL6 and MAF have been identified as master regulators of their differentiation [12,13,14,15,16]

Methods

Results

Discussion

Conclusion