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1.
J Clin Invest ; 134(14)2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38833303

RESUMO

Cutaneous leishmaniasis caused by Leishmania parasites exhibits a wide range of clinical manifestations. Although parasites influence disease severity, cytolytic CD8+ T cell responses mediate disease. Although these responses originate in the lymph node, we found that expression of the cytolytic effector molecule granzyme B was restricted to lesional CD8+ T cells in Leishmania-infected mice, suggesting that local cues within inflamed skin induced cytolytic function. Expression of Blimp-1 (Prdm1), a transcription factor necessary for cytolytic CD8+ T cell differentiation, was driven by hypoxia within the inflamed skin. Hypoxia was further enhanced by the recruitment of neutrophils that consumed oxygen to produce ROS and ultimately increased the hypoxic state and granzyme B expression in CD8+ T cells. Importantly, lesions from patients with cutaneous leishmaniasis exhibited hypoxia transcription signatures that correlated with the presence of neutrophils. Thus, targeting hypoxia-driven signals that support local differentiation of cytolytic CD8+ T cells may improve the prognosis for patients with cutaneous leishmaniasis, as well as for other inflammatory skin diseases in which cytolytic CD8+ T cells contribute to pathogenesis.


Assuntos
Linfócitos T CD8-Positivos , Leishmaniose Cutânea , Neutrófilos , Fator 1 de Ligação ao Domínio I Regulador Positivo , Animais , Leishmaniose Cutânea/imunologia , Leishmaniose Cutânea/patologia , Leishmaniose Cutânea/parasitologia , Camundongos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Neutrófilos/imunologia , Neutrófilos/patologia , Neutrófilos/metabolismo , Humanos , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Fator 1 de Ligação ao Domínio I Regulador Positivo/imunologia , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Granzimas/metabolismo , Granzimas/imunologia , Granzimas/genética , Hipóxia Celular/imunologia , Feminino
2.
bioRxiv ; 2023 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-37904953

RESUMO

Cutaneous leishmaniasis caused by Leishmania parasites exhibits a wide range of clinical manifestations. Although parasites influence disease severity, cytolytic CD8 T cell responses mediate disease. While these responses originate in the lymph node, we find that expression of the cytolytic effector molecule granzyme B is restricted to lesional CD8 T cells in Leishmania - infected mice, suggesting that local cues within inflamed skin induce cytolytic function. Expression of Blimp-1 ( Prdm1 ), a transcription factor necessary for cytolytic CD8 T cell differentiation, is driven by hypoxia within the inflamed skin. Hypoxia is further enhanced by the recruitment of neutrophils that consume oxygen to produce reactive oxygen species, ultimately increasing granzyme B expression in CD8 T cells. Importantly, lesions from cutaneous leishmaniasis patients exhibit hypoxia transcription signatures that correlate with the presence of neutrophils. Thus, targeting hypoxia-driven signals that support local differentiation of cytolytic CD8 T cells may improve the prognosis for patients with cutaneous leishmaniasis, as well as other inflammatory skin diseases where cytolytic CD8 T cells contribute to pathogenesis.

3.
Nat Commun ; 14(1): 1652, 2023 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-36964178

RESUMO

During intracellular infection, T follicular helper (TFH) and T helper 1 (TH1) cells promote humoral and cell-mediated responses, respectively. Another subset, CD4-cytotoxic T lymphocytes (CD4-CTLs), eliminate infected cells via functions typically associated with CD8+ T cells. The mechanisms underlying differentiation of these populations are incompletely understood. Here, we identify the transcription factor Aiolos as a reciprocal regulator of TFH and CD4-CTL programming. We find that Aiolos deficiency results in downregulation of key TFH transcription factors, and consequently reduced TFH differentiation and antibody production, during influenza virus infection. Conversely, CD4-CTL programming is elevated, including enhanced Eomes and cytolytic molecule expression. We further demonstrate that Aiolos deficiency allows for enhanced IL-2 sensitivity and increased STAT5 association with CD4-CTL gene targets, including Eomes, effector molecules, and IL2Ra. Thus, our collective findings identify Aiolos as a pivotal regulator of CD4-CTL and TFH programming and highlight its potential as a target for manipulating CD4+ T cell responses.


Assuntos
Linfócitos T Auxiliares-Indutores , Fatores de Transcrição , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Interleucina-2/genética , Interleucina-2/metabolismo , Linfócitos T CD8-Positivos , Linfócitos T CD4-Positivos , Diferenciação Celular
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