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Regulatory T cell suppression is potentiated by target T cells in a cell contact, IL-35- and IL-10-dependent manner.

ABSTRACT: Regulatory T cells (T(reg)) are believed to suppress conventional T cell (T(conv)) proliferation in vitro in a contact-dependent, cytokine-independent manner, based in part on experiments in which T(reg) and T(conv) are separated by a permeable membrane. We show that the production of IL-35, a novel inhibitory cytokine expressed by natural T(reg), increases substantially following contact with T(conv). Surprisingly, T(reg) were able to mediate potent suppression of T(conv) across a permeable membrane when placed in direct contact with T(conv) in the upper chamber of a Transwell plate. Suppression was IL-35 and IL-10 dependent, and T(conv) activation was required for maximal potentiation of T(reg) suppression. These data suggest that it is the induction of suppression, rather than the function of T(reg) that is obligatorily contact dependent.

SUBMITTER: Collison LW

PROVIDER: S-EPMC2698997 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Regulatory T cell suppression is potentiated by target T cells in a cell contact, IL-35- and IL-10-dependent manner.

Collison Lauren W LW Pillai Meenu R MR Chaturvedi Vandana V Vignali Dario A A DA

Journal of immunology (Baltimore, Md. : 1950) 20090501 10

Regulatory T cells (T(reg)) are believed to suppress conventional T cell (T(conv)) proliferation in vitro in a contact-dependent, cytokine-independent manner, based in part on experiments in which T(reg) and T(conv) are separated by a permeable membrane. We show that the production of IL-35, a novel inhibitory cytokine expressed by natural T(reg), increases substantially following contact with T(conv). Surprisingly, T(reg) were able to mediate potent suppression of T(conv) across a permeable mem ...[more]

PMID: 19414764

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Project description:Bacterial infections remain a significant cause of adverse pregnancy outcomes. Ascending infection of group B streptococcus (GBS) or Streptococcus agalactiae from the lower genital tract to the amniotic cavity leads to fetal injury, preterm births, or stillbirths. Factors increasing the invasive potential of bacteria at the maternal-fetal interface are poorly understood. Previous studies have indicated that the GBS hyaluronidase (HylB) can enhance systemic infection by breaking down host hyaluronan into disaccharides that dampen protective TLR2 and TLR4 signaling. Here, we examined the importance of hyaluronan receptors such as TLR2, TLR4, and CD44 in defense against GBS infections during pregnancy. While HylB promoted ascending GBS infection in wild-type (WT) and CD44-deficient mice, surprisingly, mice lacking both TLR2 and TLR4 (TLR2/4) were able to curtail these infections. Interleukin-10 (IL-10) and IL-10-expressing macrophages were significantly increased in the uterine tissues of WT mice during infection with HylB-proficient GBS compared with those of TLR2/4-deficient mice, and this likely promotes immune suppression and GBS dissemination. Consistent with these observations, pregnant IL-10-deficient mice exhibited diminished GBS ascension and dissemination. Similarly, the administration of a blocking antibody against the IL-10 receptor (IL-10R) in WT mice diminished ascending GBS infection. Collectively, these observations indicate that HylB promotes immune suppression in a TLR2/4- and IL-10-dependent manner to enhance the invasive potential of GBS during pregnancy-associated infections. IMPORTANCE Bacteria such as GBS can cause infections during pregnancy leading to preterm births, stillbirths, and neonatal infections. The interaction between host and bacterial factors during infections in the placenta is not fully understood. GBS secretes a hyaluronidase enzyme that is thought to digest host hyaluronan into immunosuppressive disaccharides that dampen TLR2/4 signaling, leading to increased bacterial dissemination and adverse outcomes. In this study, we show that GBS HylB mediates immune suppression and promotes bacterial infection during pregnancy that requires TLR2, TLR4, and IL-10. Understanding the interaction between host and bacterial factors can inform future therapeutic strategies to mitigate GBS infections.

Dataset Information

Regulatory T cell suppression is potentiated by target T cells in a cell contact, IL-35- and IL-10-dependent manner.

Publications

Regulatory T cell suppression is potentiated by target T cells in a cell contact, IL-35- and IL-10-dependent manner.

Similar Datasets

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