T follicular helper cell heterogeneity: Time, space, and function

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Abstract

T follicular helper (Tfh) cells play a crucial role in orchestrating the humoral arm of adaptive immune responses. Mature Tfh cells localize to follicles in secondary lymphoid organs (SLOs) where they provide help to B cells in germinal centers (GCs) to facilitate immunoglobulin affinity maturation, class switch recombination, and generation of long-lived plasma cells and memory B cells. Beyond the canonical GC Tfh cells, it has been increasingly appreciated that the Tfh phenotype is highly diverse and dynamic. As naïve CD4+ T cells progressively differentiate into Tfh cells, they migrate through a variety of microanatomical locations to obtain signals from other cell types, which in turn alters their phenotypic and functional profiles. We herein review the heterogeneity of Tfh cells marked by the dynamic phenotypic changes accompanying their developmental program. Focusing on the various locations where Tfh and Tfh-like cells are found, we highlight their diverse states of differentiation. Recognition of Tfh cell heterogeneity has important implications for understanding the nature of T helper cell identity specification, especially the plasticity of the Tfh cells and their ontogeny as related to conventional T helper subsets.

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The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function.

Andrew N. Macintyre, Valerie Gerriets, Amanda G Nichols … (2014)

CD4 T cell activation leads to proliferation and differentiation into effector (Teff) or regulatory (Treg) cells that mediate or control immunity. While each subset prefers distinct glycolytic or oxidative metabolic programs in vitro, requirements and mechanisms that control T cell glucose uptake and metabolism in vivo are uncertain. Despite expression of multiple glucose transporters, Glut1 deficiency selectively impaired metabolism and function of thymocytes and Teff. Resting T cells were normal until activated, when Glut1 deficiency prevented increased glucose uptake and glycolysis, growth, proliferation, and decreased Teff survival and differentiation. Importantly, Glut1 deficiency decreased Teff expansion and the ability to induce inflammatory disease in vivo. Treg cells, in contrast, were enriched in vivo and appeared functionally unaffected and able to suppress Teff, irrespective of Glut1 expression. These data show a selective in vivo requirement for Glut1 in metabolic reprogramming of CD4 T cell activation and Teff expansion and survival. Copyright © 2014 Elsevier Inc. All rights reserved.

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Cxc Chemokine Receptor 5 Expression Defines Follicular Homing T Cells with B Cell Helper Function

Patrick Schaerli, Katharina Willimann, Aloïs B. Lang … (2000)

Leukocyte traffic through secondary lymphoid tissues is finely tuned by chemokines. We have studied the functional properties of a human T cell subset marked by the expression of CXC chemokine receptor 5 (CXCR5). Memory but not naive T cells from tonsils are CXCR5+ and migrate in response to the B cell–attracting chemokine 1 (BCA-1), which is selectively expressed by reticular cells and blood vessels within B cell follicles. Tonsillar CXCR5+ T cells do not respond to other chemokines present in secondary lymphoid tissues, including secondary lymphoid tissue chemokine (SLC), EBV-induced molecule 1 ligand chemokine (ELC), and stromal cell–derived factor 1 (SDF-1). The involvement of tonsillar CXCR5+ T cells in humoral immune responses is suggested by their localization in the mantle and light zone germinal centers of B cell follicles and by the concomitant expression of activation and costimulatory markers, including CD69, HLA-DR, and inducible costimulator (ICOS). Peripheral blood CXCR5+ T cells also belong to the CD4+ memory T cell subset but, in contrast to tonsillar cells, are in a resting state and migrate weakly to chemokines. CXCR5+ T cells are very inefficient in the production of cytokines but potently induce antibody production during coculture with B cells. These properties portray CXCR5+ T cells as a distinct memory T cell subset with B cell helper function, designated here as follicular B helper T cells (TFH).

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PD-1 regulates germinal center B cell survival and the formation and affinity of long-lived plasma cells

Kim L. Good-Jacobson, Courtney Szumilas, Lieping Chen … (2010)

Memory B and plasma cells (PCs) are generated in the germinal center (GC). As PD-1 is highly expressed in T follicular helper cells (TFH), we investigated the role of PD-1 signaling in the humoral response. We found that PD-L1 and PD-L2 are upregulated on GC B cells. Pdcd1lg2 −/− , CD274 −/− Pdcd1lg2 −/− and Pdcd1 −/− mice had reduced numbers of long-lived PCs. The mechanism involved increased GC cell death and decreased TFH cytokine production in the absence of PD-1; the effect was selective, as remaining PCs had higher affinity. PD-1 expression on T cells and PD-L2 expression on B cells controlled TFH and PC numbers. Thus, PD-1 regulates selection and survival in the GC, impacting the quantity and quality of long-lived PCs.