RESUMO
Immune homeostasis in peripheral tissues is, to a large degree, maintained by the differentiation and action of regulatory T cells (Treg) specific for tissue Ags. Using a novel mouse model, we have studied the differentiation of naive CD4+ T cells into Foxp3+ Treg in response to a cutaneous Ag (OVA). We found that expression of OVA resulted in fatal autoimmunity and in prevention of peripheral Treg generation. Inhibiting mTOR activity with rapamycin rescued the generation of Foxp3+ T cells. When we varied the level of Ag expression to modulate TCR signaling, we found that low Ag concentrations promoted the generation of Foxp3+ T cells, whereas high levels expanded effector T cells and caused severe autoimmunity. Our findings indicate that the expression level of tissue Ag is a key determinant of the balance between tissue-reactive effector and peripheral Foxp3+ T cells, which determines the choice between tolerance and autoimmunity.
Assuntos
Doenças Autoimunes/imunologia , Diferenciação Celular/imunologia , Ativação Linfocitária , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Animais , Doenças Autoimunes/patologia , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Ovalbumina/genética , Ovalbumina/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Sirolimo/farmacologia , Pele/imunologia , Pele/patologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismoRESUMO
Muscular injury associated with local inflammatory reaction frequently occurs in sports medicine, but the individual response and capacity of regeneration vary among subjects. Inflammatory cytokines are probably implicated in activation of repair mechanisms by specifically influencing tissue microenvironment. This work aimed to compare muscle tissue repair in different mouse lineages. We used C57BL/6 and BALB/c mice genetically predisposed to either Type1 or Type2 cytokine production. The role of Type1 cytokines was also investigated in C57IFN-γ (IFNγ-KO) and C57IL-12 (IL12-KO) knockout mice. Participation of T lymphocytes was assessed in athymic BALB/c nude (nu/nu) mice. Muscular lesion was induced with bupivacaine injection in the Triceps brachii muscle. BALB/c mice showed marked collagen deposition and increased TGF-ß mRNA content, contrasting with mild fibrosis observed in C57BL/6 mice. C57-IFNγ-KO mice, exhibited pronounced fibrosis, but IL12-KO collagen deposition was similar to that of C57. Twenty-four hours after lesion, C57BL/6 and BALB/c(nu/nu) presented numerous regenerating myofibres and marked increase of metalloprotease-9 activity compared with BALB/c. These data support that skeletal muscle remodelling is greatly influenced by the genetic backgrounds, shedding light on the molecular mechanisms influencing differential muscular remodelling and tissue regeneration among individuals.
