The origins, function, and regulation of T follicular helper cells

Abstract

The generation of high-affinity antibodies (Abs) plays a critical role in the neutralization and clearance of pathogens and subsequent host survival after natural infection with a variety of microorganisms. Most currently available vaccines rely on the induction of long-lived protective humoral immune responses by memory B cells and plasma cells, underscoring the importance of Abs in host protection. Ab responses against most antigens (Ags) require interactions between B cells and CD4+ T helper cells, and it is now well recognized that T follicular helper cells (Tfh) specialize in providing cognate help to B cells and are fundamentally required for the generation of T cell–dependent B cell responses. Perturbations in the development and/or function of Tfh cells can manifest as immunopathologies, such as immunodeficiency, autoimmunity, and malignancy. Unraveling the cellular and molecular requirements underlying Tfh cell formation and maintenance will help to identify molecules that could be targeted for the treatment of immunological diseases that are characterized by insufficient or excessive Ab responses.

The value of rituximab treatment in primary Sjögren's syndrome

“…Patients with pSS have elevated proportions of circulating T follicular helper (cTfh) cells, defined as CXCR5 + PD-1 + CD45RA − CD4 + cells, compared with healthy controls [17,33,34]. The B cell hyperactivity that is present in pSS patients may favor differentiation of Tfh cells through secretion of IL-6 by activated B cells in conjunction with high expression of costimulatory molecules (e.g., CD40, ICOS-L) [35,36]. Tfh cells subsequently activate B cells and promote germinal center formation and plasma cell formation [36], providing a positive-feedback loop.…”

“…The B cell hyperactivity that is present in pSS patients may favor differentiation of Tfh cells through secretion of IL-6 by activated B cells in conjunction with high expression of costimulatory molecules (e.g., CD40, ICOS-L) [35,36]. Tfh cells subsequently activate B cells and promote germinal center formation and plasma cell formation [36], providing a positive-feedback loop. We have recently shown that cTfh cells, and to a smaller extent also Th17 cells, are reduced by rituximab [17].…”

Follicular helper T cells may play an important role in the severity of primary Sjögren's syndrome

“…cluster of differentiation (CD)40L and signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) which are critical in T-B cell interaction [9,[12][13][14][15][16]. In the follicles, [20].…”

iNKT‐cell help to B cells: A cooperative job between innate and adaptive immune responses

“…This leads to Ag internalization, presentation of the processed Ag peptides into MHC class II (MHC II) molecules, and migration of the activated B cells to the border of the T-B-cell zone [4]. T FH cells are induced in the T-cell zone by dendritic cells (DCs) that have internalized and present peptides of the same Ags [6]. T FH -cell differentiation requires upregulation of the transcriptional repressor B-cell lymphoma-6 (BCL-6) and costimulation with CD28 and interleukin-21 (IL-21) [6], and results in the upregulation of CXC chemokine receptor 5 (CXCR5), iNKT cells iNKT cells are a unique T-cell subset characterized by the expression of a conserved invariant T-cell receptor (TCR) Vα chain (Vα14Jα18 in mice; Vα24Jα18 in humans), paired with a restricted repertoire of diverse TCR Vβ chains (Vβ8.2, Vβ7, or Vβ2 in mice; Vβ11 in humans) [12,13].…”

“…T FH cells are induced in the T-cell zone by dendritic cells (DCs) that have internalized and present peptides of the same Ags [6]. T FH -cell differentiation requires upregulation of the transcriptional repressor B-cell lymphoma-6 (BCL-6) and costimulation with CD28 and interleukin-21 (IL-21) [6], and results in the upregulation of CXC chemokine receptor 5 (CXCR5), iNKT cells iNKT cells are a unique T-cell subset characterized by the expression of a conserved invariant T-cell receptor (TCR) Vα chain (Vα14Jα18 in mice; Vα24Jα18 in humans), paired with a restricted repertoire of diverse TCR Vβ chains (Vβ8.2, Vβ7, or Vβ2 in mice; Vβ11 in humans) [12,13]. The semi-invariant TCR recognizes CD1d [14], a member of the CD1 family of nonpolymorphic, MHC-I-like lipid Ag presenting molecules that is expressed on monocytes, DCs, B cells, and some nonhematopoietic cells (reviewed in [15]).…”