Regulatory mechanisms that control T‐follicular helper and T‐helper 1 cell flexibility

Abstract

Following antigenic stimulation, CD4 þ T cells have the potential to differentiate into a number of specialized effector cell subtypes. To date, much progress has been made in defining the basic molecular mechanisms that regulate initial helper T-cell differentiation decisions. Emerging research in the field is now uncovering more complexity in the series of events that control helper T-cell commitment decisions than was previously appreciated. During the commitment process, helper T cells need to integrate both signals derived from the T-cell receptor and from the surrounding microenvironment. These external signals are then translated into internal changes in gene expression potential to ultimately define the functional characteristics of the cell. In this review, this topic will be discussed from the perspective of T-follicular helper (Tfh) and T-helper type 1 (Th1) cell differentiation. The focus will be on examining how the cytokine environment is perceived by signaling through signal transducer and activator of transcription (STAT) family proteins to initiate fate choices. The activities of STAT proteins are then in turn translated into changes in the molecular balance between B-cell lymphoma 6 (Bcl-6) and T-box expressed in T cells (T-bet), the helper T-cell lineage-specifying transcription factors that regulate Tfh and Th1 effector cell differentiation, respectively. Collectively, the knowledge of the molecular pathways that regulate Tfh and Th1 commitment have provided insight into the relationship between these two specialized helper T-cell subtypes and the potential for flexibility in their gene programs.

Cholesterol-Independent Suppression of Lymphocyte Activation, Autoimmunity, and Glomerulonephritis by Apolipoprotein A-I in Normocholesterolemic Lupus-Prone Mice

“…Based on our finding that Th1 and Tfh cells are reduced in Sle123 →ApoA-I tg mice (Figure 4B–C), it is possible that PPARγ activation by 13-HODE and/or 9-HODE in lymphocytes may be a mechanism for ApoA-I mediated immune suppression, reducing T cell activation and subsequent expansion of Th1 and Tfh CD4 + T cells. Indeed, effects of ApoA-I on the lipid environment of CD4 + T lymphocytes and other immune cell-types in SLE may have a significant influence over the repertoire of transcription factors and cytokine signals that control CD4 + T cell differentiation into Th and effector subsets (33, 60). It is therefore important to determine whether 13-HODE and 9-HODE are generated intrinsically by the lymphocytes themselves or if they are derived from nearby innate immune cells such as macrophages which have been reported to produce these oxylipids in response to inflammatory stimuli through 12/15-LO enzyme activation to inhibit T cell activation and differentiation through PPARγ (53).…”

Transcriptional and epigenetic regulation of T‐helper lineage specification

“…Gene expression profiles and functions of Tfh cells compared to other effector Th cells make them a functionally distinct Th-cell subtype (185). Differentiation of Tfh cells is induced by IL6 and IL21, and the cells express C-X-C type chemokine receptor, CXCR5 and lineage-specific TF BCL6 (187)(188)(189)(190)(191)(192). Depletion of BCL6 in CD4 + T cells results in a failure to produce Tfh cells, whereas BCL6 overexpression promotes Tfh cell development indicating that BCL6 is necessary and sufficient for Tfh cell differentiation (83,193,194).…”

Global transcriptome analysis and enhancer landscape of human primary T follicular helper and T effector lymphocytes

“…[1][2][3][4][5][6][7][8] Tfh cells also secrete cytokines that enable B-cell isotype class switching appropriate to invading pathogens. 5,8,9 Tfh cells can be distinguished from other Th cells by downregulation of P-selectin glycoprotein ligand 1 (PSGL-1), required for their emigration from T-cell zones of secondary lymphoid organs toward the B-cell follicle, and by their sustained expression of the transcriptional repressor B-cell lymphoma 6 (BCL6), the C-X-C chemokine receptor type 5 (CXCR5) needed for their migration into the follicle, and the programmed cell death receptor (PD-1) necessary for proper B-cell maturation therein in GCs.…”