Aberrant TGF-β signaling reduces T regulatory cells in ICAM-1-deficient mice, increasing the inflammatory response to Mycobacterium tuberculosis

Abstract

Foxp3+ T regulatory cells are required to prevent autoimmune disease, but also prevent clearance of some chronic infections. While natural T regulatory cells are produced in the thymus, TGF-beta1 signaling combined with T-cell receptor signaling induces the expression of Foxp3 in CD4+ T cells in the periphery. We found that ICAM-1-/- mice have fewer T regulatory cells in the periphery than WT controls, due to a role for ICAM-1 in induction of Foxp3 expression in response to TGF-beta1. Further investigation revealed a functional deficiency in the TGF-beta1-induced translocation of phosphorylated Smad3 from the cytoplasmic compartment to the nucleus in ICAM-1-deficient mice. This impairment in the TGF-beta1 signaling pathway is most likely responsible for the decrease in T regulatory cell induction in the absence of ICAM-1. We hypothesized that in the presence of an inflammatory response, reduced production of inducible T regulatory cells would be evident in ICAM-1-/- mice. Indeed, following Mycobacterium tuberculosis infection, ICAM-1-/- mice had a pronounced reduction in T regulatory cells in the lungs compared with control mice. Consequently, the effector T-cell response and inflammation were greater in the lungs of ICAM-1-/- mice, resulting in morbidity due to overwhelming pathology.

Regulation of CD4+ T Cells by Pleural Mesothelial Cells via Adhesion Molecule-Dependent Mechanisms in Tuberculous Pleurisy

“…Further studies suggested that ICAM-1/LFA-1 ligation favors human Th1 development [27,28]. Recently, it has been demonstrated that ICAM-1/LFA-1 stimulated human and mouse T cells refractory to TGF-β-mediated induction of FoxP3 and Th17 differentiation [29], while some other studies supported our results showing that Treg amplification was dependent on ICAM-1 [30,31], and deficiency of ICAM-1 might result in overwhelming inflammation [30]. We considered that the origin or activatory state of antigen presenting cells, the responder T cell density, and the doses of anti‒ICAM-1 or ‒VCAM-1 mAb might account for the discrepancies, and further investigations were needed.…”

JAK2-STAT3 Blockade by AG490 Suppresses Autoimmune Arthritis in Mice via Reciprocal Regulation of Regulatory T Cells and Th17 Cells

“…ICOS and PD-1 are required for the development of Tregs and their regulation of effector T cells (40,41). ICAM-1 is associated with TGF-b-induced Foxp3 expression (42), and CD103 has been used as a marker of in vivoactivated CD4 +…”

Macrophages and control of granulomatous inflammation in tuberculosis

“…79 However, modulation of the Treg population in certain mice leads to increased mortality because of enhanced inflammation in the lungs. 80 Tregs are good candidates for balancing immune responses through their interactions with T cells and necessary for preventing autoimmune diseases. Although Tregs are often only considered in their capacity to downregulate effector T-cell responses, and therefore exacerbate the infection, in chronic or persistent infections, these cells may be crucial players in preventing pathology.…”