T follicular helper cell programming by cytokine‐mediated events

Abstract

Summary CD4+ T cells, or T helper cells, are critical mediators and coordinators of adaptive immunity. Unique effector T helper cell populations have been identified that perform distinct functions in response to pathogenic infection. The T follicular helper (Tfh) cells are one such subset, which has been identified as the primary T-cell population responsible for interacting with B cells to promote effective antibody-mediated immune responses. Since their initial description at the turn of the century, and subsequent classification as a distinct T helper cell subset, there has been substantial interest in elucidating the regulatory mechanisms that govern Tfh cell formation. The collective insight from this body of work has demonstrated that Tfh cell differentiation is a complex and multistage process regulated by a litany of cell-intrinsic and cell-extrinsic factors. As with the development of the other recognized T helper cell subsets, specific cytokines exercise prominent roles in both the positive and negative regulation of Tfh cell development. However, the exact composition of, and stage-specific requirements for, these environmental factors in the governance of Tfh cell differentiation remain incompletely understood. In this review, we summarize what is known regarding the role of cytokines in both the promotion and inhibition of Tfh cell differentiation and function.

Integrated STAT3 and Ikaros Zinc Finger Transcription Factor Activities Regulate Bcl-6 Expression in CD4+ Th Cells

“…As discussed previously, signals from environmental cytokines are key determinants of T helper cell differentiation. These include IL-6 and IL-2, which have been shown to positively and negatively influence T FH development, respectively (21, 57, 58). Therefore, we wanted to assess whether Aiolos or Ikaros may play a broader role in promoting T FH cell differentiation by regulating the expression of the receptors for these cytokines.…”

“…STAT3, STAT5) at the Bcl6 promoter is an important contributor to the regulation of Bcl-6 expression (21, 57, 58). Unexpectedly, our findings demonstrate that STAT3 physically interacts with Aiolos.…”

“…The differential effects of these cytokines are propagated through the activation of specific STAT factors known to associate with regulatory regions within the Bcl6 gene locus. Specifically, STAT1, STAT3, and STAT4 have been shown to positively regulate Bcl-6 expression, while STAT5 is a demonstrated repressor of Bcl-6(21, 31). Beyond STAT factors, additional transcriptional regulators including Batf and Tcf-1 have been shown to induce Bcl-6 expression (32-35).…”

Multifaceted role of IL‐21 in rheumatoid arthritis: Current understanding and future perspectives

“…Follicular T helper cells (Tfh) are the major T cell lineage which promotes B cells maturation and proliferation to produce antibodies for regulating humoral immune response (Qi, ; Walters & Vinuesa, ). During a disease condition, Tfh cells produce large amounts of IL‐21 for B cell differentiation to mediate pathogenic clearance after which it is subdued (Read, Powell, & Oestreich, ). Bryant et al () reported that huge quantities of immunoglobulin (Ig) subtypes (IgG, IgM, and IgA) were mediated through the presence of IL‐21 as a precursor for Tfh cell activation.…”

From dendritic cells to B cells dysfunctions during HIV‐1 infection: T follicular helper cells at the crossroads

“…The T‐cell–B‐cell interactions through surface proteins provide further signals allowing pre‐Tfh cells to enter the B‐cell follicles and facilitate the germinal center (GC) reaction. Several cytokines, such as interleukin‐6 (IL‐6), IL‐21 and IL‐12 have been involved in the development of Tfh cells …”