CD4+ T cells participate in the immune response of several lung diseases

Author(s)

Igor Santiago de Carvalho

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2022-03-31

Examining board members

Maria Regina D'Imperio Lima; José Carlos Farias Alves Filho; Vania Luiza Deperon Bonato; Jean Pierre Schatzmann Peron

• Advisor: Maria Regina D'Imperio Lima; Elena Lassounskaia

Abstract

In infectious diseases that affect the lungs, CD4&#43 T cells response can generate protection or aggravation. During tuberculosis caused by Mycobacterium tuberculosis, CD4&#43 T cell response is regulated by the lung tissue, which controls the excessive entry of these cells into the lung parenchyma. This is a mechanism that prevents damage to organs that have low regenerative capacity. However, some severe diseases can induce unregulated entry of T cells, as in infections with mycobacterial hypervirulent strains and the Influenza virus. In this context, it is still unclear which mechanisms regulates the entry of these cells into the lung tissue during these infections and their consequences. Therefore, this study sought to understand the role of resident CD4&#43 T cells in generating lung damage and worsening lung infections and the mechanisms involved in this process. For this, we used models of severe pulmonary infection induced by Mycobacterium bovis (MP287) and Influenza virus (PR8). Infection with the MP287 strain induces severe lung injury that is associated with high numbers of resident CD4&#43 T cells in C57BL/6 (WT) mice. CD4&#43 T cell depletion 21 days p.i. prevented the worsening of infection. Next, we transferred intermediate (1x106) and high (3x106) numbers of CD4&#43 T cells to infected Cd4-/- mice. As a result, only mice that received high numbers of CD4&#43 T cells developed severe tuberculosis. Severe tuberculosis induces the release of high levels of extracellular ATP (eATP) that is recognized by the purinergic receptor P2RX7. The eATP-P2RX7 interaction is crucial for the generation of resident T cells. Additionally, P2RX7 is highly expressed on lung-resident CD4&#43 T cells during MP287 infection. In this way, we evaluated whether P2RX7 expression can regulate CD4&#43 T cell residence during MP287 infection. P2rx7-/- and Cd4creP2rx7fl/fl mice were infected and developed mild tuberculosis associated with low numbers of lung-resident CD4&#43 T cells. After co-transfer of CD4&#43 T cells isolated from WT and P2rx7-/- mice to Cd4-/- mice, we found mostly WT CD4&#43 T cells in the lung parenchyma, while P2rx7-/- CD4&#43 T cells were mainly located in the vasculature. To assess whether this phenomenon is an infection-specific or not, we used the model of viral infection with the PR8 strain. P2RX7 deficiency in T cells prevented severe inflammation and fibrosis formation in the lung during PR8 infection. In addition, lung-resident CD4&#43 T cells are reduced in P2RX7-deficient mice. To understand the molecular pathways involved in this phenomenon, lung-resident CD4&#43 T cells were isolated from the lung 7 days p.i. with PR8 to RNAseq analysis. The data demonstrate that P2RX7-deficient resident CD4&#43 T cells have reduced expression of genes related to cell migration and proliferation such as: Cxcr3 and Mki67. These data indicate that the eATP-P2RX7 interaction in the lung during infections induces the accumulation of CD4&#43 T cells in the tissue, increasing the migration and proliferation of these cells. To understand what is the source of eATP in the lung tissue that CD4&#43 T cells use during PR8 infection, we infected Panexin 1 (Panx-1) mice deficient full or only in T cells. The number of lung-resident CD4&#43 T cells were reduced only with total Panx-1 deficiency. Therefore, these data indicate that the paracrine recognition of eATP via P2RX7 regulates the residence of CD4&#43 T cells in the lung, determining the fate of local infectious diseases. (AU)

• FAPESP's process: 19/24700-8 - Role of P2X7 receptor on parenchymal and intravascular CD4 T cell response in a Severe Experimental Tuberculosis model
• Grantee: Igor Santiago de Carvalho
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)