The Balance of Protein Kinase C and Calcium Signaling Directs T Cell Subset Development

The development of inflammatory diseases depends on complex interactions between several genes and various environmental factors. Discovering new genetic risk factors and understanding the mechanisms whereby they influence disease development is of paramount importance. We previously reported that deficiency in Themis1, a new actor of TCR signaling, impairs regulatory T cell (Treg) function and predisposes Brown–Norway (BN) rats to spontaneous inflammatory bowel disease (IBD). In this study, we reveal that the epistasis between Themis1 and Vav1 controls the occurrence of these phenotypes. Indeed, by contrast with BN rats, Themis1 deficiency in Lewis rats neither impairs Treg suppressive functions nor induces pathological manifestations. By using congenic lines on the BN genomic background, we show that the impact of Themis1 deficiency on Treg suppressive functions depends on a 117-kb interval coding for a R63W polymorphism that impacts Vav1 expression and functions. Indeed, the introduction of a 117-kb interval containing the Lewis Vav1-R63 variant restores Treg function and protects Themis1-deficient BN rats from spontaneous IBD development. We further show that Themis1 binds more efficiently to the BN Vav1-W63 variant and is required to stabilize its recruitment to the transmembrane adaptor LAT and to fully promote the activation of Erk kinases. Together, these results highlight the importance of the signaling pathway involving epistasis between Themis1 and Vav1 in the control of Treg suppressive function and susceptibility to IBD development.

Section: Discussionmentioning

confidence: 99%

An Epistatic Interaction between Themis1 and Vav1 Modulates Regulatory T Cell Function and Inflammatory Bowel Disease Development

Pedros

Gaud

Bernard

et al. 2015

“…nAChR subtypes, causing the opening of receptor ion channels, leading to subtle changes in intracellular levels of calcium ions (32,33). Normal maturation of thymocytes involves TCR ligation, which itself induces calcium ion influx (34,35). In this fashion exogenous nicotine may mimic TCR signals via ionotropic means and effectively change the way T cells normally mature.…”

Section: Discussionmentioning

confidence: 99%

Effects of Nicotine Exposure on T Cell Development in Fetal Thymus Organ Culture: Arrest of T Cell Maturation

Middlebrook

Martina

Chang

et al. 2002

There is evidence for both physiological functions of the natural neurotransmitter, acetylcholine, and pharmacological actions of the plant alkaloid, nicotine, on the development and function of the immune system. The effects of continuous exposure to nicotine over a 12-day course of fetal thymus organ culture (FTOC) were studied, and thymocytes were analyzed by flow cytometry. In the presence of very low concentrations of nicotine many more immature T cells (defined by low or negative TCR expression) and fewer mature T cells (intermediate or high expression of TCR) were produced. In addition, the numbers of cells expressing CD69 and, to a lesser extent, CD95 (Fas) were increased. These effects took place when fetal thymus lobes from younger (13–14 days gestation) pups were used for FTOC. If FTOC were set up using tissue from older (15–16 days gestation pups), nicotine had little effect, suggesting that it may act only on immature T cell precursors. Consistent with an increase in immature cells, the expression of recombinase-activating genes was found to be elevated. Nicotine effects were partially blocked by the simultaneous addition of the nicotinic antagonist d-tubocurarine. Furthermore, d-tubocurarine alone blocked the development of both immature and mature murine thymocytes, suggesting the presence of an endogenous ligand that may engage nicotinic acetylcholine receptors on developing thymocytes and influence the course of normal thymic ontogeny.

“…Previous studies have demonstrated that the strength of the signals mediated through TCRs can influence Th cell lineage commitment (5,(13)(14)(15)(16). It is possible that activation of T cells via TCRs may polarize the cells toward being Th1 or Th2 cells, and these cells further differentiate and proliferate in response to IL-12 or IL-4, respectively (17).…”

Section: D4mentioning

confidence: 99%

Polarized Development of Memory Cell-Like IFN-γ-Producing Cells in the Absence of TCR ζ-Chain

Krymskaya

Lee

Zhong

et al. 2005

TCR/CD3 complex-mediated signals play critical roles in regulating CD4+ Th cell differentiation. In this report, we have examined the in vivo role of a key TCR/CD3 complex molecule ζ-chain in regulating the differentiation of Th cells. We have studied T cells from ζ-chain-deficient mice (ζKO mice), ζ-chain-bearing mice (ζ+ mice), and from ζKO mice expressing a FcRγ chain transgene (FcRγTG, ζKO mice). Our results demonstrated that, compared with those of control mice, CD4+ T cells and not CD8+ T cells from ζKO mice were polarized into IFN-γ-producing cells. Some of these IFN-γ-producing cells could also secrete IL-10. Interestingly, ζKO mouse T cells produced IFN-γ even after they were cultured in a Th2 condition. Our studies to determine the molecular mechanisms underlying the polarized IFN-γ production revealed that the expression level of STAT4 and T-bet were up-regulated in freshly isolated T cells from ζKO mice. Further studies showed that noncultured ζKO mice CD4+ T cells and thymocytes bore a unique memory cell-like CD44high, CD62Llow/neg phenotype. Altogether, these results suggest that, in the absence of the ζ-chain, CD4+ T cells develop as polarized IFN-γ-producing cells that bear a memory cell-like phenotype. The ζ-chain-bearing T cells may produce a large amount of IFN-γ only after they are cultured in a condition favoring Th1 cell differentiation. This study may provide important implications for the down-regulation of ζ-chain in T cells of patients bearing a variety of tumors, chronic inflammatory and infectious diseases.