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1.
bioRxiv ; 2023 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-37808649

RESUMO

Maintenance of immune homeostasis to the intestinal mictrobiota is dependent on a population of effector regulatory T (eTreg) cells that develop from microbiota-reactive induced (i)Treg cells. A cardinal feature of eTreg cells is their production of IL-10, which plays a non-redundant role in immune tolerance of commensal microbes. Here, we identify an unexpected role for IL-2-induced Stat3 signaling to program iTreg cells for eTreg cell differentiation and Il10 transcriptional competency. IL-2 proved to be both necessary and sufficient for eTreg cell development - contingent on Stat3 output of the IL-2 receptor coordinate with IL-2 signaling during early Treg cell commitment. Induction of iTreg cell programming in absence of IL-2-induced Stat3 signaling resulted in impaired eTreg cell differentiation and a failure to produce IL-10. An IL-2 mutein with reduced affinity for the IL-2Rγ (γ c ) chain was found to have blunted IL-2R Stat3 output, resulting in a deficiency of Il10 transcriptional programming that could not be fully rescued by Stat3 signaling subsequent to an initial window of iTreg cell differentiation. These findings expose a heretofore unappreciated role of IL-2 signaling that acts early to program subsequent production of IL-10 by developing eTreg cells, with broad implications for IL-2-based therapeutic interventions in immune-mediated diseases.

2.
Sci Immunol ; 7(76): eabo0777, 2022 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-36206355

RESUMO

Both higher- and lower-affinity self-reactive CD4+ T cells are expanded in autoimmunity; however, their individual contribution to disease remains unclear. We addressed this question using peptide-MHCII chimeric antigen receptor (pMHCII-CAR) T cells to specifically deplete peptide-reactive T cells in mice. Integration of improvements in CAR engineering with TCR repertoire analysis was critical for interrogating in vivo the role of TCR affinity in autoimmunity. Our original MOG35-55 pMHCII-CAR, which targeted only higher-affinity TCRs, could prevent the induction of experimental autoimmune encephalomyelitis (EAE). However, pMHCII-CAR enhancements to pMHCII stability, as well as increased survivability via overexpression of a dominant-negative Fas, were required to target lower-affinity MOG-specific T cells and reverse ongoing clinical EAE. Thus, these data suggest a model in which higher-affinity autoreactive T cells are required to provide the "activation energy" for initiating neuroinflammatory injury, but lower-affinity cells are sufficient to maintain ongoing disease.


Assuntos
Encefalomielite Autoimune Experimental , Receptores de Antígenos Quiméricos , Animais , Antígenos , Autoimunidade , Linfócitos T CD4-Positivos , Camundongos , Peptídeos , Receptores de Antígenos de Linfócitos T , Receptores de Antígenos Quiméricos/genética
3.
Immunity ; 54(11): 2547-2564.e7, 2021 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-34715017

RESUMO

Cryptosporidium can cause severe diarrhea and morbidity, but many infections are asymptomatic. Here, we studied the immune response to a commensal strain of Cryptosporidium tyzzeri (Ct-STL) serendipitously discovered when conventional type 1 dendritic cell (cDC1)-deficient mice developed cryptosporidiosis. Ct-STL was vertically transmitted without negative health effects in wild-type mice. Yet, Ct-STL provoked profound changes in the intestinal immune system, including induction of an IFN-γ-producing Th1 response. TCR sequencing coupled with in vitro and in vivo analysis of common Th1 TCRs revealed that Ct-STL elicited a dominant antigen-specific Th1 response. In contrast, deficiency in cDC1s skewed the Ct-STL CD4 T cell response toward Th17 and regulatory T cells. Although Ct-STL predominantly colonized the small intestine, colon Th1 responses were enhanced and associated with protection against Citrobacter rodentium infection and exacerbation of dextran sodium sulfate and anti-IL10R-triggered colitis. Thus, Ct-STL represents a commensal pathobiont that elicits Th1-mediated intestinal homeostasis that may reflect asymptomatic human Cryptosporidium infection.


Assuntos
Criptosporidiose/imunologia , Criptosporidiose/parasitologia , Cryptosporidium/imunologia , Células Dendríticas/imunologia , Interações Hospedeiro-Parasita/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/parasitologia , Células Th1/imunologia , Animais , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Homeostase , Mucosa Intestinal/metabolismo , Camundongos , Microbiota , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Células Th1/metabolismo
4.
Proc Natl Acad Sci U S A ; 116(48): 24221-24230, 2019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31699814

RESUMO

The success of B cell depletion therapies and identification of leptomeningeal ectopic lymphoid tissue (ELT) in patients with multiple sclerosis (MS) has renewed interest in the antibody-independent pathogenic functions of B cells during neuroinflammation. The timing and location of B cell antigen presentation during MS and its animal model experimental autoimmune encephalomyelitis (EAE) remain undefined. Using a new EAE system that incorporates temporal regulation of MHCII expression by myelin-specific B cells, we observed the rapid formation of large B cell clusters in the spinal cord subarachnoid space. Neutrophils preceded the accumulation of meningeal B cell clusters, and inhibition of CXCR2-mediated granulocyte trafficking to the central nervous system reduced pathogenic B cell clusters and disease severity. Further, B cell-restricted very late antigen-4 (VLA-4) deficiency abrogated EAE dependent on B cell antigen presentation. Together, our findings demonstrate that neutrophils coordinate VLA-4-dependent B cell accumulation within the meninges during neuroinflammation, a key early step in the formation of ELT observed in MS.


Assuntos
Linfócitos B/imunologia , Encefalomielite Autoimune Experimental/imunologia , Integrina alfa4beta1/metabolismo , Meninges/imunologia , Esclerose Múltipla/patologia , Animais , Apresentação de Antígeno , Linfócitos B/patologia , Quimiocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/patologia , Feminino , Integrina alfa4beta1/imunologia , Tecido Linfoide/imunologia , Tecido Linfoide/patologia , Masculino , Meninges/patologia , Meningite/imunologia , Meningite/patologia , Camundongos Endogâmicos C57BL , Esclerose Múltipla/imunologia , Células Mieloides/patologia , Neutrófilos/imunologia , Neutrófilos/patologia , Coelhos , Receptores de Interleucina-8B/metabolismo , Espaço Subaracnóideo/patologia
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