CTLA-4 regulates the requirement for cytokine-induced signals in TH2 lineage commitment

Abstract

The relative importance of the cytokine milieu versus cytolytic T lymphocyte-associated antigen 4 (CTLA-4) and T cell receptor signal strength on T cell differentiation remains unclear. Here we have generated mice deficient for signal transducer and activator of transcription 6 (STAT6) and CTLA-4 to determine the role of CTLA-4 in cytokine-driven T cell differentiation. CTLA-4-deficient T cells bypass the need for STAT6 in the differentiation of T helper type 2 (T(H)2) cells. T(H)2 differentiation of cells deficient for both STAT6 and CTLA-4 is accompanied by induction of GATA-3 and the migration of T(H)2 cells to peripheral tissues. CTLA-4 deficiency also affects the balance of the nuclear factors NFATc1 and NFATc2, and enhances activation of NF-kappaB. These results suggest that CTLA-4 has a critical role in T cell differentiation and that STAT6-dependent T(H)2 lineage commitment and stabilization can be bypassed by increasing the strength of signaling through the T cell receptor.

CTLA-4 controls the thymic development of both conventional and regulatory T cells through modulation of the TCR repertoire

“…The length of the CDR3 region has previously been implicated in the differentiation of Tconv cells to either a Th1 or Th2 phenotype (53). Similarly, CTLA-4-deficient mice have been shown to exhibit a skewed repertoire of Th1, Th2, and Th17 cells, which was also reported here for Tg4 CTLA-4KO mice (28,(35)(36)(37)). In our model, CDR3α using the endogenous TRAV13 showed a greater diversity in length in Treg cells than Tconv cells, which was previously found by one group (43), although other groups have found a comparable (44) or lower (45) diversity in different models.…”

“…This effect was unexpected, because CTLA-4 is not expressed on splenic Tconv cells until at least 24 h after activation (34). Accordingly, alterations in IL-4 and IL-17 production in other CTLA-4KO models did not occur until after a second TCR stimulation (28,(35)(36)(37). The observed effect on IL-10 production has not been reported previously to our knowledge.…”

Targeting of CD25 and Glucocorticoid-Induced TNF Receptor Family-Related Gene-Expressing T Cells Differentially Modulates Asthma Risk in Offspring of Asthmatic and Normal Mother Mice

“…Consistent with the fact that CTLA-4 inhibits Th2 differentiation (49,50) and participates in tolerance mechanisms (51,52), CTLA-4 blockade with UC10-4F10 mAb exacerbated asthma syndrome in normal pups (53) without clearly ameliorating the susceptibility of asthma-prone offspring.…”

Coexpression of CD25 and OX40 (CD134) Receptors Delineates Autoreactive T-cells in Type 1 Diabetes

“…Furthermore, our data provide evidence for an important role of costimulatory signaling in the development of autoimmune diabetes, thus allowing timely therapeutic interventions to halt ␤-cell destruction to be designed (35)(36)(37). …”