Interleukin-2 Inhibits Germinal Center Formation by Limiting T Follicular Helper Cell Differentiation

Ballesteros-Tato, André; León, Beatriz; Graf, Beth A.; Moquin, Amy; Adams, Pamela S.; Lund, Frances E.; Randall, Troy D.

doi:10.1016/j.immuni.2012.02.012

Cited by 450 publications

(482 citation statements)

References 65 publications

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“…Recent studies have implicated novel T helper cell subsets as initiators of ELF formation. Given the role that cytokines play in the regulation of T helper cell differentiation and effector function, a number of cytokines have now been linked with the control of ELF s. For example, cytokines involved in the regulation of T helper type 17 (Th17) cell responses ( IL ‐6, IL ‐21, IL ‐23, IL ‐27, IL ‐2, IL ‐22, IL ‐17)23, 137, 139, 145, 148, 152 and follicular T helper (Tfh) cell responses [ IL ‐6, IL ‐21, Type I interferons ( IFN s), IL ‐27, IL ‐2]137, 139, 146, 147, 150 are emerging as regulators of lymphoid neogenesis. Here we highlight cytokines that may positively (red) and negatively (blue) control ELF s based on their ability to regulate effector T‐cell populations involved in ELF development or function.…”

Section: Cellular Initiators Of Ectopic Lymphoneogenesismentioning

confidence: 99%

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

2015

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SummaryLymphoid neogenesis is traditionally viewed as a pre‐programmed process that promotes the formation of lymphoid organs during development. Here, the spatial organization of T and B cells in lymph nodes and spleen into discrete structures regulates antigen‐specific responses and adaptive immunity following immune challenge. However, lymphoid neogenesis is also triggered by chronic or persistent inflammation. Here, ectopic (or tertiary) lymphoid organs frequently develop in inflamed tissues as a response to infection, auto‐immunity, transplantation, cancer or environmental irritants. Although these structures affect local immune responses, the contribution of these lymphoid aggregates to the underlining pathology are highly context dependent and can elicit either protective or deleterious outcomes. Here we review the cellular and molecular mechanisms responsible for ectopic lymphoid neogenesis and consider the relevance of these structures in human disease.

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Section: Cellular Initiators Of Ectopic Lymphoneogenesismentioning

confidence: 99%

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

2015

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“…PD-1 impairs IL-2 signaling through the CD25 receptor (39), which normally favors blimp-1 over bcl-6 expression and T effector over T FH cell development (36). In this context, CD25 negatively regulates T FH cell development, and therefore, we hypothesized that CD25 would negatively regulate iNKT FH cell development.…”

Section: Noncognate Inkt Cell Help Induces Higher Numbers Of T Fh Celmentioning

confidence: 99%

“…Both of these conclusions are complicated by the fact that PD-1 is highly expressed by CD4 + CXCR5 + ICOS + T follicular regulatory (T FR ) cells, which (32) express Foxp3 + and inhibit germinal center responses (33)(34)(35). At the same time, IL-2 has been found to signal through CD25 to negatively regulate bcl-6 expression and inhibit T FH cell development (36). This effect was mediated independently of Treg cells, relying instead on indirect up-regulation of CD25 on T cells.…”

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confidence: 99%

Cognate interaction with iNKT cells expands IL-10–producing B regulatory cells

Vomhof-DeKrey

Yates

Hägglöf

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Successful induction of B-cell activation and memory depends on help from CD4 + T cells. Invariant natural killer T (iNKT) cells (glycolipid-specific, CD1d-restricted innate lymphocytes) provide both cognate (direct) and noncognate (indirect) helper signals to enhance B-cell responses. Both forms of iNKT-cell help induce primary humoral immune responses, but only noncognate iNKT-cell help drives humoral memory and plasma cells. Here, we show that iNKT cognate help for B cells is fundamentally different from the help provided by conventional CD4 + T cells. Cognate iNKT-cell help drives an early, unsustained germinal center B-cell expansion, less reduction of T follicular regulatory cells, an expansion of marginal zone B cells, and early increases in regulatory IL-10-producing B-cell numbers compared with noncognate activation. These results are consistent with a mechanism whereby iNKT cells preferentially provide an innate form of help that does not generate humoral memory and has important implications for the application of glycolipid molecules as vaccine adjuvants.

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“…Conversely, Tfh cells are CD25 lo and BCL6 is known to be a reciprocal regulator of BLIMP-1 (2). As a result, Tfh cells are directly inhibited by IL-2/STAT5-driven induction of BLIMP-1 expression (14,15). In addition, Tfr cells themselves have been described to express BLIMP-1, but its deletion causes their expansion, suggesting that BLIMP-1 acts to inhibit their formation (10), whereas loss of BCL6 results in increased expression of BLIMP-1 by Treg cells (7).…”

mentioning

confidence: 99%

A distinct subpopulation of CD25⁻T-follicular regulatory cells localizes in the germinal centers

Wing

Kitagawa

Locci

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

166

236

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T-follicular helper (Tfh) cells differentiate through a multistep process, culminating in germinal center (GC) localized GC-Tfh cells that provide support to GC-B cells. T-follicular regulatory (Tfr) cells have critical roles in the control of Tfh cells and GC formation. Although Tfh-cell differentiation is inhibited by IL-2, regulatory T (Treg) cell differentiation and survival depend on it. Here, we describe a CD25− subpopulation within both murine and human PD1+CXCR5+Foxp3+ Tfr cells. It is preferentially located in the GC and can be clearly differentiated from CD25+ non–GC-Tfr, Tfh, and effector Treg (eTreg) cells by the expression of a wide range of molecules. In comparison to CD25+ Tfr and eTreg cells, CD25− Tfr cells partially down-regulate IL-2–dependent canonical Treg features, but retain suppressive function, while simultaneously up-regulating genes associated with Tfh and GC-Tfh cells. We suggest that, similar to Tfh cells, Tfr cells follow a differentiation pathway generating a mature GC-localized subpopulation, CD25− Tfr cells.

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Interleukin-2 Inhibits Germinal Center Formation by Limiting T Follicular Helper Cell Differentiation

Cited by 450 publications

References 65 publications

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

Cognate interaction with iNKT cells expands IL-10–producing B regulatory cells

A distinct subpopulation of CD25⁻T-follicular regulatory cells localizes in the germinal centers

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Interleukin-2 Inhibits Germinal Center Formation by Limiting T Follicular Helper Cell Differentiation

Cited by 450 publications

References 65 publications

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

Cognate interaction with iNKT cells expands IL-10–producing B regulatory cells

A distinct subpopulation of CD25−T-follicular regulatory cells localizes in the germinal centers

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A distinct subpopulation of CD25⁻T-follicular regulatory cells localizes in the germinal centers