Complement receptor type 1 (CR1/CD35) expressed on activated human CD4+ T cells contributes to generation of regulatory T cells.
The role of complement in the regulation of T cell immunity has been highlighted recently by several groups. We were prompted to reinvestigate the role of complement receptor type 1 (CR1, CD35) [corrected] in human T cells based on our earlier data showing that activated human T cells produce C3 (Torok et al. (2012) [48]) and also by results demonstrating that engagement of Membrane Cofactor Protein (MCP, CD46) induces a switch of anti-CD35-activated [corrected] helper T cells into regulatory T cells (Kemper et al. (2003) [17]). We demonstrate here that co-ligation of CD46 and CD35, [corrected] the two C3b-binding structures present on activated CD4+ human T cells significantly enhances CD25 expression, elevates granzyme B production and synergistically augments cell proliferation. The role of CR1 in the development of the Treg phenotype was further confirmed by demonstrating that its engagement enhances IL-10 production and reduces IFNγ release by the activated CD4+ T cells in the presence of excess IL-2. The functional in vivo relevance of our findings was highlighted by the immunohistochemical staining of tonsils, revealing the presence of CD4/CD35 [corrected] double positive lymphocytes mainly in the inter-follicular regions where direct contact between CD4+ T cells and B lymphocytes occurs. Regarding the in vivo relevance of the complement-dependent generation of regulatory T cells in secondary lymphoid organs we propose a scenario shown in the figure. The depicted process involves the sequential binding of locally produced C3 fragments to CD46 and CD35 [corrected] expressed on activated T cells, which - in the presence of excess IL-2 - leads to the development of Treg cells.
MTA-ELTE Immunology Research Group, Budapest, Hungary.
Katalin
K
Török
Department of Pathology, Medical Center, University of Debrecen, Hungary.
Balázs
B
Dezső
MTA-ELTE Immunology Research Group, Budapest, Hungary.
András
A
Bencsik
MTA-ELTE Immunology Research Group, Budapest, Hungary.
Barbara
B
Uzonyi
MTA-ELTE Immunology Research Group, Budapest, Hungary; Department of Immunology, Eötvös Loránd University, Budapest, Hungary. Electronic address: anna.erdei@ttk.elte.hu.
Anna
A
Erdei
D000954:Antigens, Surface / Q000378:metabolism; D015415:Biomarkers; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000096:biosynthesis; D015870:Gene Expression; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics* / Q000276:immunology*; D014066:Palatine Tonsil / Q000166:cytology / Q000276:immunology; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D017463:Receptors, Complement 3b / Q000235:genetics* / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism
D000954:Antigens, Surface; D015415:Biomarkers; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; D017463:Receptors, Complement 3b
CD4+ human T cells; CR1 (CD35) expression; Synergism with MCP (CD46); Treg differentiation