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  • Regulating the regulators

    20 November 2017

  • Human MAIT and CD8αα cells develop from a pool of type-17 precommitted CD8<sup>+</sup>T cells

    20 March 2018

    Human mucosal associated invariant T (MAIT) CD8 + and Tc17 cells are important tissue-homing cell populations, characterized by high expression of CD161 ( ++ ) and type-17 differentiation, but their origins and relationships remain poorly defined. By transcriptional and functional analyses, we demonstrate that a pool of polyclonal, precommitted type-17CD161 ++ CD8αβ + T cells exist in cord blood, from which a prominent MAIT cell(TCR Vα7.2 + ) population emerges postnatally. During this expansion, CD8αα T cells appear exclusively within aCD161 ++ CD8 + /MAIT subset, sharing cytokine production, chemokine-receptor expression, TCR-usage, and transcriptional profiles with their CD161 ++ CD8αβ + counterparts. Our data demonstrate the origin and differentiation pathway of MAIT-cells from a naive type-17 precommitted CD161 ++ CD8 + T-cell pool and the distinct phenotype and function of CD8αα cells in man. © 2012 by The American Society of Hematology.

  • Human MAIT and CD8αα cells develop from a pool of type-17 precommitted CD8+ T cells.

    3 April 2018

    Human mucosal associated invariant T (MAIT) CD8(+) and Tc17 cells are important tissue-homing cell populations, characterized by high expression of CD161 ((++)) and type-17 differentiation, but their origins and relationships remain poorly defined. By transcriptional and functional analyses, we demonstrate that a pool of polyclonal, precommitted type-17 CD161(++)CD8αβ(+) T cells exist in cord blood, from which a prominent MAIT cell (TCR Vα7.2(+)) population emerges post-natally. During this expansion, CD8αα T cells appear exclusively within a CD161(++)CD8(+)/MAIT subset, sharing cytokine production, chemokine-receptor expression, TCR-usage, and transcriptional profiles with their CD161(++)CD8αβ(+) counterparts. Our data demonstrate the origin and differentiation pathway of MAIT-cells from a naive type-17 precommitted CD161(++)CD8(+) T-cell pool and the distinct phenotype and function of CD8αα cells in man.

  • A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism.

    4 April 2018

    Foxp3(+) regulatory T (T reg) cells play a key role in controlling immune pathological re actions. Many develop their regulatory activity in the thymus, but there is also evidence for development of Foxp3(+) T reg cells from naive precursors in the periphery. Recent studies have shown that transforming growth factor (TGF)-beta can promote T reg cell development in culture, but little is known about the cellular and molecular mechanisms that mediate this pathway under more physiological conditions. Here, we show that after antigen activation in the intestine, naive T cells acquire expression of Foxp3. Moreover, we identify a population of CD103(+) mesenteric lymph node dendritic cells (DCs) that induce the development of Foxp3(+) T reg cells. Importantly, promotion of T reg cell responses by CD103(+) DCs is dependent on TGF-beta and the dietary metabolite, retinoic acid (RA). These results newly identify RA as a cofactor in T reg cell generation, providing a mechanism via which functionally specialized gut-associated lymphoid tissue DCs can extend the repertoire of T reg cells focused on the intestine.

  • A mouse model of HIES reveals pro- and anti-inflammatory functions of STAT3.

    13 March 2018

    Mutations of STAT3 underlie the autosomal dominant form of hyperimmunoglobulin E syndrome (HIES). STAT3 has critical roles in immune cells and thus, hematopoietic stem cell transplantation (HSCT), might be a reasonable therapeutic strategy in this disease. However, STAT3 also has critical functions in nonhematopoietic cells and dissecting the protean roles of STAT3 is limited by the lethality associated with germline deletion of Stat3. Thus, predicting the efficacy of HSCT for HIES is difficult. To begin to dissect the importance of STAT3 in hematopoietic and nonhematopoietic cells as it relates to HIES, we generated a mouse model of this disease. We found that these transgenic mice recapitulate multiple aspects of HIES, including elevated serum IgE and failure to generate Th17 cells. We found that these mice were susceptible to bacterial infection that was partially corrected by HSCT using wild-type bone marrow, emphasizing the role played by the epithelium in the pathophysiology of HIES.

  • Helicobacter hepaticus infection in BALB/c mice abolishes subunit-vaccine-induced protection against M. tuberculosis.

    28 March 2018

    BCG, the only licensed vaccine against tuberculosis (TB), provides geographically variable protection, an effect ascribed to exposure to environmental mycobacteria (EM). Here we show that altering the intestinal microbiota of mice by early-life infection with the commensal bacterium Helicobacter hepaticus (Hh) increases their susceptibility to challenge with Mycobacterium tuberculosis (Mtb). Furthermore Hh-infected mice immunised parenterally with the recombinant subunit vaccine, human adenovirus type 5 expressing the immunodominant antigen 85A of Mtb (Ad85A), display a reduced lung immune response and protection against Mtb challenge is also reduced. Expression of interleukin 10 (IL10) messenger RNA is increased in the colon of Hh infected mice. Treatment of Hh-infected Ad85A-immunised mice with anti-IL10 receptor antibody, following challenge with Mtb, restores the protective effect of the vaccine. These data show for the first time that alteration of the intestinal microbiota by addition of a single commensal organism can profoundly influence protection induced by a TB subunit vaccine via an IL10-dependent mechanism, a result with implications for the deployment of such vaccines in the field.

  • T cells that cannot respond to TGF-beta escape control by CD4(+)CD25(+) regulatory T cells.

    3 April 2018

    CD4(+)CD25(+) regulatory T (T reg) cells play a pivotal role in control of the immune response. Transforming growth factor-beta (TGF-beta) has been shown to be required for T reg cell activity; however, precisely how it is involved in the mechanism of suppression is poorly understood. Using the T cell transfer model of colitis, we show here that CD4(+)CD45RB(high) T cells that express a dominant negative TGF-beta receptor type II (dnTbetaRII) and therefore cannot respond to TGF-beta, escape control by T reg cells in vivo. CD4(+)CD25(+) T reg cells from the thymus of dnTbetaRII mice retain the ability to inhibit colitis, suggesting that T cell responsiveness to TGF-beta is not required for the development or peripheral function of thymic-derived T reg cells. In contrast, T reg cell activity among the peripheral dnTbetaRII CD4(+)CD25(+) population is masked by the presence of colitogenic effector cells that cannot be suppressed. Finally, we show that CD4(+)CD25(+) T reg cells develop normally in the absence of TGF-beta1 and retain the ability to suppress colitis in vivo. Importantly, the function of TGF-beta1(-/-) T reg cells was abrogated by anti-TGF-beta monoclonal antibody, indicating that functional TGF-beta can be provided by a non-T reg cell source.