Thymic stromal lymphopoietin (TSLP) is a cytokine that promotes CD4+ T cell homeostasis. We now demonstrate that TSLP is required to mount a normal CD4+ T cell–mediated inflammatory response. TSLP acts directly on naive, but not, memory CD4+ T cells, and promotes their proliferation in response to antigen. In addition, TSLP exerts an effect indirectly through DCs to promote Th2 differentiation of CD4+ T cells. Correspondingly, TSLP receptor (TSLPR) knockout (KO) mice exhibit strong Th1 responses, with high levels of interleukin (IL)-12, interferon-γ, and immunoglobulin (Ig) G2a, but low production of IL-4, -5, -10, -13, and IgE; moreover, CD4+ T cells from these animals proliferate less well in response to antigen. Furthermore, TSLPR KO mice fail to develop an inflammatory lung response to inhaled antigen unless supplemented with wild-type CD4+ T cells. This underscores an important role for this cytokine in the development of inflammatory and/or allergic responses in vivo.
Bone marrow stromal cells [BMSCs; also known as mesenchymal stem cells (MSCs)] effectively suppress inflammatory responses in acute graft-versus-host disease in humans and in a number of disease models in mice. Many of the studies concluded that BMSC-driven immunomodulation is mediated by the suppression of proinflammatory Th1 responses while rebalancing the Th1/Th2 ratio toward Th2. In this study, using a ragweed induced mouse asthma model, we studied if BMSCs could be beneficial in an allergic, Th2-dominant environment. When BMSCs were injected i.v. at the time of the antigen challenge, they protected the animals from the majority of asthma-specific pathological changes, including inhibition of eosinophil infiltration and excess mucus production in the lung, decreased levels of Th2 cytokines (IL-4, IL-5, and IL-13) in bronchial lavage, and lowered serum levels of Th2 immunoglobulins (IgG1 and IgE). To explore the mechanism of the effect we used BMSCs isolated from a variety of knockout mice, performed in vivo blocking of cytokines and studied the effect of asthmatic serum and bronchoalveolar lavage from ragweed challenged animals on the BMSCs in vitro. Our results suggest that IL-4 and/or IL-13 activate the STAT6 pathway in the BMSCs resulting in an increase of their TGF-β production, which seems to mediate the beneficial effect, either alone, or together with regulatory T cells, some of which might be recruited by the BMSCs. These data suggest that, in addition to focusing on graft-versus-host disease and autoimmune diseases, allergic conditions—specifically therapy resistant asthma—might also be a likely target of the recently discovered cellular therapy approach using BMSCs.
DR3 (TRAMP, LARD, WSL-1, TNFRSF25) is a death-domain-containing tumor necrosis factor (TNF)-family receptor primarily expressed on T cells. TL1A, the TNF-family ligand for DR3, can costimulate T cells, but the physiological function of TL1A-DR3 interactions in immune responses is not known. Using DR3-deficient mice, we identified DR3 as the receptor responsible for TL1A-induced T cell costimulation and dendritic cells as the likely source for TL1A during T cell activation. Despite its role in costimulation, DR3 was not required for in vivo T cell priming, for polarization into T helper 1 (Th1), Th2, or Th17 effector cell subtypes, or for effective control of infection with Toxoplasma gondii. Instead, DR3 expression was required on T cells for immunopathology, local T cell accumulation, and cytokine production in Experimental Autoimmune Encephalomyelitis (EAE) and allergic lung inflammation, disease models that depend on distinct effector T cell subsets. DR3 could be an attractive therapeutic target for T cell-mediated autoimmune and allergic diseases.
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