Roquin Differentiates the Specialized Functions of Duplicated T Cell Costimulatory Receptor Genes Cd28 and Icos

Linterman, Michelle A.; Rigby, Robert J.; Wong, Raphael. K.; Silva, Diego Augusto Santos; Withers, David R.; Anderson, Graham; Verma, Naresh K.; Brink, Robert; Hutloff, Andreas; Goodnow, Christopher C.; Vinuesa, Carola G.

doi:10.1016/j.immuni.2008.12.015

Cited by 131 publications

(134 citation statements)

References 63 publications

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“…This is consistent with CD28 being expressed on naïve T cells while ICOS is induced following T-cell activation (59). Indeed, it was noted that restricting ICOS function to downstream of CD28 was key to maintaining two-signal control of T-cell responses (60). We now extend this concept and suggest that CD28 and ICOS function are inherently coupled.…”

Section: Discussionsupporting

confidence: 82%

See 1 more Smart Citation

CTLA-4 controls follicular helper T-cell differentiation by regulating the strength of CD28 engagement

Wang

Heuts

Ovcinnikovs

et al. 2014

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

152

151

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Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is an essential regulator of T-cell responses, and its absence precipitates lethal T-cell hyperactivity. However, whether CTLA-4 acts simply to veto the activation of certain clones or plays a more nuanced role in shaping the quality of T-cell responses is not clear. Here we report that T cells in CTLA-4-deficient mice show spontaneous Tfollicular helper (T FH ) differentiation in vivo, and this is accompanied by the appearance of large germinal centers (GCs). Remarkably, short-term blockade with anti-CTLA-4 antibody in wild-type mice is sufficient to elicit T FH generation and GC development. The latter occurs in a CD28-dependent manner, consistent with the known role of CTLA-4 in regulating the CD28 pathway. CTLA-4 can act by down-regulating CD80 and CD86 on antigen presenting cells (APCs), thereby altering the level of CD28 engagement. To mimic reduced CD28 ligation, we used mice heterozygous for CD28, revealing that the magnitude of CD28 engagement is tightly linked to the propensity for T FH differentiation. In contrast, other parameters of T-cell activation, including CD62L down-regulation and Ki67 expression, were relatively insensitive to altered CD28 level. Altered T FH generation as a result of graded reduction in CD28 was associated with decreased numbers of GC B cells and a reduction in overall GC size. These data support a model in which CTLA-4 control of immunity goes beyond vetoing T-cell priming and encompasses the regulation of T FH differentiation by graded control of CD28 engagement.ontrol of the magnitude and nature of adaptive immune responses is critical for health. The cytotoxic T-lymphocyteassociated antigen-4 (CTLA-4)/CD28 axis has long been known to control the magnitude of T-cell responses, however whether it also influences their nature has not been clear. Early studies suggested that CD28 may be particularly important for Th2 differentiation (1, 2), although others identified roles for CD28 in both Th1 and Th2 responses (3, 4). It is known that CD28 is an absolute requirement for the differentiation of follicular helper T cells (T FH s) that support germinal center (GC) formation (5, 6). However, these studies generally make use of CD28-deficient T cells, and therefore, results may reflect a failure of the cells to properly activate, proliferate, or survive, particularly given the known contribution of CD28 to these processes.A key outstanding question is whether CD28 costimulation in vivo is more complex than a binary checkpoint for T-cell priming. It is clear that expression of costimulatory ligands on antigen presenting cells (APCs) fluctuates in response to environmental stimuli, being up-regulated by inflammatory cytokines and TLR agonists and down-regulated by Treg-expressed CTLA-4 (7-11). Thus, variable levels of costimulatory ligands will be available for CD28 binding depending on the microenvironmental context. However, whether this simply alters the number of T cells that achieve the required threshold to commit to a resp...

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Section: Discussionsupporting

confidence: 82%

“…Accordingly, CD28 −/− mice overexpressing ICOS as a consequence of roquin mutation do not form spontaneous GCs (although GCs can be induced by immunization) (60). Thus, overstimulation of CD28, as a consequence of CTLA-4 deficiency or blockade ( Figs.…”

Section: Discussionmentioning

confidence: 97%

CTLA-4 controls follicular helper T-cell differentiation by regulating the strength of CD28 engagement

Wang

Heuts

Ovcinnikovs

et al. 2014

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

152

151

View full text Add to dashboard Cite

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“…The prototype T-cell costimulator CD28 is also required for GC reaction, humoral immunity, and generation of T FH cells (23,24). It is puzzling that the generation of T FH requires both CD28 and ICOS, although the two costimulators have a seemingly redundant function in activating PI3K (25,26).…”

Section: Cd28 ͉ Follicular B Helper T-cell ͉ Germinal Center ͉ Icos ͉mentioning

confidence: 99%

Inducible costimulator promotes helper T-cell differentiation through phosphoinositide 3-kinase

Gigoux

Shang

Pak

et al. 2009

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

208

258

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The T-cell costimulatory receptors, CD28 and the inducible costimulator (ICOS), are required for the generation of follicular B helper T cells (T FH) and germinal center (GC) reaction. A common signal transducer used by CD28 and ICOS is the phosphoinositide 3-kinase (PI3K). Although it is known that CD28-mediated PI3K activation is dispensable for GC reaction, the role of ICOS-driven PI3K signaling has not been defined. We show here that knock-in mice that selectively lost the ability to activate PI3K through ICOS had severe defects in T FH generation, GC reaction, antibody class switch, and antibody affinity maturation. In preactivated CD4 ؉ T cells, ICOS delivered a potent PI3K signal that was critical for the induction of the key T FH cytokines, IL-21 and IL-4. Under the same settings, CD28 was unable to activate PI3K but supported a robust secondary expansion of T cells. Thus, our results demonstrate a nonredundant function of ICOS-PI3K pathway in the generation of T FH and suggest that CD28 and ICOS play differential roles during a multistep process of T FH differentiation.CD28 ͉ follicular B helper T-cell ͉ germinal center ͉ ICOS ͉ PI3K

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“…17 However, CD28-mediated responses, the generation of Tfh cells and germinal-center formation become independent of CD28 and dependent on ICOS when the E3 ubiquitin ligase Roquin is mutated. 29 ICOS belongs to the CD28 family and is expressed on activated T cells. 30,31 while its ligand, B7h, is broadly expressed on APCs in nonlymphoid tissues.…”

Section: Differentiation Of Tfh Cellsmentioning

confidence: 99%

Understanding the development and function of T follicular helper cells

2010

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A fundamental function of T helper (Th) cells is to regulate B-cell proliferation and immunoglobulin class switching, especially in the germinal centers. Th1 and Th2 lineages of CD4 1 T cells have long been considered to play an essential role in helping B cells by promoting the production immunoglobulin G2a (IgG2a) and IgG1/IgE, respectively. Recently, it has become clear that a subset CD4 1 T cells, named T follicular helper (Tfh) cells, is critical to B-cell response induction. In this review, we summarize the latest advances in our understanding of the regulation of Tfh cell differentiation, the relationship of Tfh cells to other CD41 T-cell lineages, and the role of Tfh cells in health and disease.

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Roquin Differentiates the Specialized Functions of Duplicated T Cell Costimulatory Receptor Genes Cd28 and Icos

Cited by 131 publications

References 63 publications

CTLA-4 controls follicular helper T-cell differentiation by regulating the strength of CD28 engagement

CTLA-4 controls follicular helper T-cell differentiation by regulating the strength of CD28 engagement

Inducible costimulator promotes helper T-cell differentiation through phosphoinositide 3-kinase

Understanding the development and function of T follicular helper cells

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