Abstract
CD4 T follicular helper (Tfh) cells play a unique and essential role in the generation of B cell responses in the lymph node microenvironment. Here we sought to determine if differential expression of PD-1 could be used to delineate Tfh cells in rhesus macaque lymph nodes (LN). CD3+CD4+ T cells were found to harbor a unique subset of cells that expressed the Program death-1 (PD-1) receptor at significantly high levels that were enriched in the LN compartment as compared to peripheral blood. The LN CD4+PD1hi T cells expressed a predominantly CD28+CD95+ central memory phenotype and were CCR7loICOShiBcl6hi. Additionally, CD4+PD1hi T cells preferentially expressed high levels of CXCR5 and IL-21 and significantly correlated with Bcl6+Ki-67+ IgG+ B cells. As Bcl6 is primarily expressed by proliferating B cells within active germinal centers, our results suggest that LN CD4+PD1hi T cells likely localize to active GC regions, a characteristic that is attributable to Tfh cells. Overall, our findings suggest that high levels of PD-1 expression on CD4+ T cells in LN of rhesus macaques can serve as a valuable marker to identify Tfh cells and has implications for studying the role of Tfh cells in Human immunodeficiency virus (HIV), Simian immunodeficiency virus (SIV) and other infectious diseases that use the rhesus macaque model.
Highlights
CD4 T cells are a heterogeneous mix of lineages such as Thelper-1 & 2 (Th1 & Th2), T-helper-17 (Th17), T-regulatory cells (Tregs) and T-follicular helper cells (Tfh) that have specialized functions during an immune response [1]
We show that Tfh cells in rhesus macaque lymph nodes (LN) can be delineated based on the high expression of program death receptor-1 (PD-1) and these CD4+PD-1hi T cells inherently express high levels of CXCR5 and IL-21 and display a phenotype that is similar to Tfh cells in mouse and humans
Tfh cells play a critical role in immunity and delineating these cell subsets have relied on using a combination of markers such as
Summary
CD4 T cells are a heterogeneous mix of lineages such as Thelper-1 & 2 (Th1 & Th2), T-helper-17 (Th17), T-regulatory cells (Tregs) and T-follicular helper cells (Tfh) that have specialized functions during an immune response [1]. Tfh cells are a major source of IL-21 in germinal centers [7] where it plays an essential role in increasing Bcl expression within B cells and the formation of germinal centers [10,13] and mediating B cell differentiation and maturation [4]. Recent studies [14,15] have shown that Tfh cells were expanded during simian immunodeficiency virus (SIV) infections in rhesus macaques and these expanded Tfh cells likely played a role in B cell dyregulation seen in these macaques. We sought to determine if differential expression of PD-1 was sufficient to phenotypically delineate Tfh cells in rhesus macaques. We show that Tfh cells in rhesus macaque LN can be delineated based on the high expression of PD-1 and these CD4+PD-1hi T cells inherently express high levels of CXCR5 and IL-21 and display a phenotype that is similar to Tfh cells in mouse and humans. We found a significantly high positive correlation between CD4+PD-1hi T cells and Bcl6+Ki67+IgG+ B cells indicating that both these populations of cells likely co-associate within the GC regions of LN
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