CXCR3 chemokine receptor contributes to specific CD8(+) T cell activation by pDC during infection with intracellular pathogens

Author(s)

Pontes Ferreira, Camila ^[1] ; Moro Cariste, Leonardo de ^[2] ; Henrique Noronha, Isau ^[1] ; Fernandes Durso, Danielle ^[3] ; Lannes-Vieira, Joseli ^[4] ; Ramalho Bortoluci, Karina ^[5] ; Araki Ribeiro, Daniel ^[2] ; Golenbock, Douglas ^[3] ; Gazzinelli, Ricardo Tostes ^[3] ; Vasconcelos, Jose Ronnie Carvalho de ^{[2, 1]}

Affiliation

^[1] Univ Fed Sao Paulo, Dept Microbiol Immunol & Parasitol, Sao Paulo - Brazil

^[2] Univ Fed Sao Paulo, Dept Biosci, Santos, SP - Brazil

^[3] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA - USA

^[4] Fiocruz MS, Lab Biol Interact, Inst Oswaldo Cruz, Rio De Janeiro - Brazil

^[5] Univ Fed Sao Paulo, Dept Biol Sci, Sao Paulo - Brazil

• Document type: Journal article
• Source: PLoS Neglected Tropical Diseases; v. 14, n. 6 JUN 2020.
• Web of Science Citations: 0

Abstract

Chemokine receptor type 3 (CXCR3) plays an important role in CD8(+)T cells migration during intracellular infections, such asTrypanosoma cruzi. In addition to chemotaxis, CXCR3 receptor has been described as important to the interaction between antigen-presenting cells and effector cells. We hypothesized that CXCR3 is fundamental toT.cruzi-specific CD8(+)T cell activation, migration and effector function. Anti-CXCR3 neutralizing antibody administration to acutelyT.cruzi-infected mice decreased the number of specific CD8(+)T cells in the spleen, and those cells had impaired in activation and cytokine production but unaltered proliferative response. In addition, anti-CXCR3-treated mice showed decreased frequency of CD8(+)T cells in the heart and numbers of plasmacytoid dendritic cells in spleen and lymph node. As CD8(+)T cells interacted with plasmacytoid dendritic cells during infection byT.cruzi, we suggest that anti-CXCR3 treatment lowers the quantity of plasmacytoid dendritic cells, which may contribute to impair the prime of CD8(+)T cells. Understanding which molecules and mechanisms guide CD8(+)T cell activation and migration might be a key to vaccine development against Chagas disease as those cells play an important role inT.cruziinfection control. Author summary Inflammatory chemokine receptors such as CXCR3 play an important role in T lymphocytes migration into an infected tissue during Th1 response. Recently, the role of CXCR3 as a co-stimulatory molecule was demonstrated, and T lymphocytes from CXCR3 deficient mice had impaired effector function. CXCR3 receptor was highly expressed on specific CD8(+)T cells after challenge withT.cruzi, and the hypothesis of that molecule is important for CD8(+)T cells activation, migration and functionality was raised. We used the anti-CXCR3 neutralizing antibody approach and demonstrated that C57BL/6 treated mice died very quickly due toT.cruziinfection, and specific CD8(+)T cells had decreased effector phenotyping, cytokine production, and cytotoxicity. In addition, anti-CXCR3 treatment decreased the number of dendritic plasmacytoid cells in the lymphoid tissues. The lower quantity of dendritic plasmacytoid cells in those tissues might contribute to the decrease in CD8(+)T cells activation. Overall, CXCR3 molecule seems to be an important molecule to be explored during vaccine against Chagas disease strategies. (AU)

• FAPESP's process: 18/15607-1 - Role of specific CD4+ and CD8+ T cells generated by different vaccination protocols against experimental Trypanosoma cruzi infection
• Grantee: Jose Ronnie Carvalho de Vasconcelos
• Support Opportunities: Research Grants - Young Investigators Grants - Phase 2
• FAPESP's process: 15/08814-2 - Role of integrin receptors and chemokines in the migration of specific CD8+ T cells generated by genetic immunization with ASP -2 Trypanosoma cruzi
• Grantee: Camila Pontes Ferreira
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 19/17994-5 - Role of the CX3CR1 chmokine receptor and LFA-1 integrin in the differentiation and activation of CD8 T lymphocytes during Trypanosoma cruzi infection
• Grantee: Leonardo Moro Cariste
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 16/02840-4 - Role of pharmacological inhibitor mTOR rapamycin in response of memory CD8+ T cells induced by heterologous prime-boost immunization
• Grantee: Barbara Ferri Moraschi
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)