Dataset Information

Calcineurin B in CD4⁺ T Cells Prevents Autoimmune Colitis by Negatively Regulating the JAK/STAT Pathway.

ABSTRACT: Calcineurin (Cn) is a protein phosphatase that regulates the activation of the nuclear factor of activated T-cells (NFAT) family of transcription factors, which are key regulators of T-cell development and function. Here, we generated a conditional Cnb1 mouse model in which Cnb1 was specifically deleted in CD4⁺ T cells (Cnb1^CD4 mice) to delineate the role of the Cn-NFAT pathway in immune homeostasis of the intestine. The Cnb1^CD4 mice developed severe, spontaneous colitis characterized at the molecular level by an increased T helper-1-cell response but an unaltered regulatory T-cell compartment. Antibiotic treatment ameliorated the intestinal inflammation observed in Cnb1^CD4 mice, suggesting that the microbiota contributes to the onset of colitis. CD4⁺ T cells isolated from Cnb1^CD4 mice produced high levels of IFN? due to increased activation of the JAK2/STAT4 pathway induced by IL-12. Our data highlight that Cn signaling in CD4⁺ T cells is critical for intestinal immune homeostasis in part by inhibiting IL-12 responsiveness of CD4⁺ T cells.

SUBMITTER: Mencarelli A

PROVIDER: S-EPMC5826051 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Calcineurin B in CD4+ T Cells Prevents Autoimmune Colitis by Negatively Regulating the JAK/STAT Pathway.

Mencarelli Andrea A Vacca Maurizio M Khameneh Hanif Javanmard HJ Acerbi Enzo E Tay Alicia A Zolezzi Francesca F Poidinger Michael M Mortellaro Alessandra A

Frontiers in immunology 20180219

Calcineurin (Cn) is a protein phosphatase that regulates the activation of the nuclear factor of activated T-cells (NFAT) family of transcription factors, which are key regulators of T-cell development and function. Here, we generated a conditional Cnb1 mouse model in which Cnb1 was specifically deleted in CD4+ T cells (Cnb1CD4 mice) to delineate the role of the Cn-NFAT pathway in immune homeostasis of the intestine. The Cnb1CD4 mice developed severe, spontaneous ...[more]

PMID: 29515579

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Project description:Most infant deaths occur in the first year of life. Yet, our knowledge of immune development during this period is scarce and derived from cord blood (CB) only. To more effectively combat pediatric diseases, a deeper understanding of the kinetics and the factors that regulate the maturation of immune functions in early life is needed. Increased disease susceptibility of infants is generally attributed to T helper 2-biased immune responses. The differentiation of CD4+ T cells along a specific T helper cell lineage is dependent on the pathogen type, and on costimulatory and cytokine signals provided by antigen-presenting cells. Cytokines also regulate many other aspects of the host immune response. Therefore, toward the goal of increasing our knowledge of early immune development, we defined the temporal development of the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signaling function of CD4+ T cells using cross-sectional blood samples from healthy infants ages 0 (birth) to 14 months. We specifically focused on cytokines important in T cell differentiation (IFN-γ, IL-12, and IL-4) or in T cell survival and expansion (IL-2 and IL-7) in infant CD4+ T cells. Independent of the cytokine tested, JAK/STAT signaling in infant compared to adult CD4+ T cells was impaired at birth, but increased during the first year, with the most pronounced changes occurring in the first 6 months. The relative change in JAK/STAT signaling of infant CD4+ T cells with age was distinct for each cytokine tested. Thus, while about 60% of CB CD4+ T cells could efficiently activate STAT6 in response to IL-4, less than 5% of CB CD4+ T cells were able to activate the JAK/STAT pathway in response to IFN-γ, IL-12 or IL-2. By 4-6 months of age, the activation of the cytokine-specific STAT molecules was comparable to adults in response to IL-4 and IFN-γ, while IL-2- and IL-12-induced STAT activation remained below adult levels even at 1 year. These results suggest that common developmental and cytokine-specific factors regulate the maturation of the JAK/STAT signaling function in CD4+ T cells during the first year of life.

Dataset Information

Calcineurin B in CD4⁺ T Cells Prevents Autoimmune Colitis by Negatively Regulating the JAK/STAT Pathway.

Publications

Calcineurin B in CD4<sup>+</sup> T Cells Prevents Autoimmune Colitis by Negatively Regulating the JAK/STAT Pathway.

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