Papel da integrina LFA-1 e do receptor de quimiocina CX3CR1 na diferenciação e ativação de linfócitos T CD8+ durante a infecção experimental pelo Trypanosoma cruzi
Data
2022-05-31
Autores
Cariste, Leonardo Moro 
Orientadores
Vasconcelos, Jose Ronnie Carvalho de
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
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Resumo
Os linfócitos T CD8+ são cruciais no controle de infecções por patógenos intracelulares como Trypanosoma cruzi. As moléculas de quimiocinas e integrinas são essenciais para a migração dos linfócitos T. No entanto, são escassos o papel dessas moléculas durante a infecção pelo T. cruzi. Os receptores de quimiocinas CX3CR1 e CXCR3 são moléculas altamente expressas na superfície dos linfócitos T CD8+ durante a infecção por patógenos intracelulares, como T. cruzi, e são importantes na ativação e diferenciação dessas células. A integrina LFA-1 também possui papel na ativação e diferenciação dos linfócitos em células de memória, uma vez que é extremamente importante no estabelecimento do contato dos linfócitos com as células apresentadoras de antígenos. Portanto nosso objetivo foi analisar as moléculas CX3CR1, CXCR3 e LFA-1 no controle da infecção, ativação, migração e diferenciação dos linfócitos T CD8. Nossos resultados demonstram que o bloqueio do CXCR3 e/ou LFA-1 levou a um aumento na carga parasitária sanguínea e tecidual além de tornar os camundongos da linhagem C57BL/6 suscetíveis à infecção pelo T. cruzi. Além disso, o bloqueio da integrina LFA-1 diminui a função efetora, citotoxicidade e migração das células T CD8+ quando comparados ao grupo infectado. Essa diminuição da função efetora também foi observada em camundongos da linhagem OT-I quando infectados com a cepa Y-OVA e tratados com anti-LFA-1. Ainda, observamos que o bloqueio do LFA-1 altera o fenótipo das células T CD8+, uma vez que os animais infectados têm um fenótipo de células T efetoras, já os tratados com LFA-1 se assemelham ao fenótipo de células naive. Também observamos que receptor de quimiocina CX3CR1 é altamente expresso nas células T CD8, porém sua ausência não comprometeu a sobrevivência e secreção de IFN- pelas células T CD8. Em conjunto, nossos dados demonstram que o LFA-1 e CXCR3 tem um papel crítico na imunidade protetora dos animais, além disso o LFA-1 exerce um papel extremamente importante nas células T CD8 auxiliando na sua migração, diferenciação e execução da sua função efetora, permitindo assim novos estudos para vacinas direcionais, com o intuito do aumento da proteção e resposta celular.
CD8+ T lymphocytes are crucial in the control of infections by intracellular pathogens such as Trypanosoma cruzi. Chemokine and integrin molecules are essential for the migration of T lymphocytes. However, the role of these molecules during T. cruzi infection is scarce. In addition, the role of these molecules in the activation and differentiation of CD8 + T lymphocytes during viral and bacterial infections has now been reported. However, the role of these molecules during T. cruzi infection is unclear. Interestingly, CX3CR1 and CXCR3 chemokine receptors are highly expressed on the surface of CD8+ T lymphocytes during infection by intracellular pathogens, such as T. cruzi, and are important in the activation and differentiation of these cells. LFA-1 integrin also plays a role in the activation and differentiation of lymphocytes in memory cells since it is extremely important in establishing contact of lymphocytes with antigen-presenting cells. Therefore, our objective was to analyze the molecules CX3CR1, CXCR3 and LFA-1 in the control of infection, activation, migration, and differentiation of CD8 T lymphocytes. Our results demonstrate that blocking CXCR3 and/or LFA-1 led to an increase in blood and tissue parasitism, in addition making C57BL/6 mice susceptible to T. cruzi infection. In addition, blocking LFA-1 integrin decreases effector function, cytotoxicity, and migration of CD8+ T cells when compared to the infected group. This reduction of effector function was also observed in OT-I mice, when infected with the Y-OVA strain and treated with anti-LFA-1. Furthermore, we observed that blocking LFA-1 alters the phenotype of CD8+ T cells, since infected animals had an effector T cell phenotype, whereas those treated with LFA-1 resemble the naive cell phenotype. We also observed that the chemokine receptor CX3CR1 is highly expressed on CD8 T cells, but its absence did not compromise the survival and secretion of IFN-γ by CD8 T cells. Together, our data demonstrate that LFA-1 and CXCR3 play a critical role in the protective immunity of animals, thus allowing new studies for directional vaccines, with the aim of increasing cellular protection and response
CD8+ T lymphocytes are crucial in the control of infections by intracellular pathogens such as Trypanosoma cruzi. Chemokine and integrin molecules are essential for the migration of T lymphocytes. However, the role of these molecules during T. cruzi infection is scarce. In addition, the role of these molecules in the activation and differentiation of CD8 + T lymphocytes during viral and bacterial infections has now been reported. However, the role of these molecules during T. cruzi infection is unclear. Interestingly, CX3CR1 and CXCR3 chemokine receptors are highly expressed on the surface of CD8+ T lymphocytes during infection by intracellular pathogens, such as T. cruzi, and are important in the activation and differentiation of these cells. LFA-1 integrin also plays a role in the activation and differentiation of lymphocytes in memory cells since it is extremely important in establishing contact of lymphocytes with antigen-presenting cells. Therefore, our objective was to analyze the molecules CX3CR1, CXCR3 and LFA-1 in the control of infection, activation, migration, and differentiation of CD8 T lymphocytes. Our results demonstrate that blocking CXCR3 and/or LFA-1 led to an increase in blood and tissue parasitism, in addition making C57BL/6 mice susceptible to T. cruzi infection. In addition, blocking LFA-1 integrin decreases effector function, cytotoxicity, and migration of CD8+ T cells when compared to the infected group. This reduction of effector function was also observed in OT-I mice, when infected with the Y-OVA strain and treated with anti-LFA-1. Furthermore, we observed that blocking LFA-1 alters the phenotype of CD8+ T cells, since infected animals had an effector T cell phenotype, whereas those treated with LFA-1 resemble the naive cell phenotype. We also observed that the chemokine receptor CX3CR1 is highly expressed on CD8 T cells, but its absence did not compromise the survival and secretion of IFN-γ by CD8 T cells. Together, our data demonstrate that LFA-1 and CXCR3 play a critical role in the protective immunity of animals, thus allowing new studies for directional vaccines, with the aim of increasing cellular protection and response
Descrição
Citação
CARISTE, Leonardo Moro. Papel da integrina LFA-1 e do receptor de quimiocina CX3CR1 na diferenciação e ativação de linfócitos T CD8+ durante a infecção experimental pelo Trypanosoma cruzi. 2022. 184 f. Tese (Doutorado em Bioprodutos e Bioprocessos) - Instituto de Saúde e Sociedade, Universidade Federal de São Paulo, Santos, 2022.