Influence of STAT3 and STAT6 Signaling Pathways in Conventional Type 1 and 2 Dendritic Cells to Prime Auxiliary T Cell Responses.

Author(s)

Fernando Bandeira Sulczewski

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2021-08-03

Examining board members

Silvia Beatriz Boscardin; Claudia Ida Brodskyn de Assis; Cristina Beatriz Cazabuena Bonorino; Ana Paula Lepique

• Advisor: Silvia Beatriz Boscardin

Abstract

In the murine spleen there are mainly two subsets of conventional dendritic cells (cDCs), one that expresses the endocytic receptor DEC205 and the alpha chain of the CD8 molecule (DEC205+CD8+), it is known as conventional type 1 dendritic cell (cDC1); another subset expresses the endocytic receptor DCIR2, but not CD8 molecule (DCIR2+CD8-), it is known as the conventional type 2 dendritic cell (cDC2). cDC1s are able to prime both CD4+ and CD8+ T lymphocytes via antigen cross-presentation of extracellular antigens. cDC2s are more associated with CD4+ T cell responses. Recently, using a strategy of antigen targetingn to each of these subsets of cDCs with chimeric monoclonal antibodies, we have identified that cDC1s and cDC2s prime different T helper cell responses. So, to better understand the mechanisms that cDC1s and cDC2s use to promote different responses, in this study we evaluated the role of STAT3 and STAT6 signaling pathways in cDC1s and cDC2s. The aim was to study the influence of these signaling pathways on the ability that each DC subset has to promote T helper cell responses. For this, we used mice in which the STAT3 molecules are deleted in the cDCs and STAT6 knockout mice. Initially, we measured whether STAT3 or STAT6 depletion would impair the differentiation of splenic cDCs, the results showed that the numbers of splenic cDC1s and cDC2s in STAT3- or STAT6-deficient mice were similar to the control group. We also analyzed whether these signaling pathways regulate the maturation of cDCs by analyzing the expression of costimulatory molecules after administration of an adjuvant, both STAT3- and STAT6-deficient cDCs matured similarly to fully competent cDCs. To study the influence of STAT signaling pathways in cDC1s and cDC2s function to prime T helper cells responses in vivo, we used a strategy of antigen targeting to cDC1s and cDC2s via DEC205 and DCIR2 receptors, respectively. Our results showed that in the absence of the STAT3 signaling pathway, antigen targeting to cDC2s induced similar frequencies of TFH cells between the groups that signal or not via the STAT3. In addition, the responses of Th1 and TFH cells promoted after antigen targeting to cDC1s were significantly lower in STAT3-deficient mice. On the other hand, when antigens were targeted to cDC2s in STAT6 KO mice, the responses of TFH cells, germinal center B cells were significantly lower. Thus, STAT3 and STAT6 signaling do not control the differentiation or maturation of splenic cDCs. The STAT3 signaling pathway stimulates cDC1s to promote Th1 and TFH cell responses. STAT6 modulates the promotion cDC2-mediated responses. (AU)

• FAPESP's process: 18/00145-2 - Influence of STAT1, STAT3, STAT5 and STAT6 signaling pathways on conventional dendritic cells in the instruction of auxiliary T cell response
• Grantee: Fernando Bandeira Sulczewski
• Support Opportunities: Scholarships in Brazil - Doctorate