Caracterização fenotípica e funcional das células T helper foliculares em indivíduos imunologicamente diferenciados: gestantes, infectadas ou não pelo HIV-1, e portadores de deficiência na produção de anticorpos

Abstract

Follicular helper T cells (TFH) are a subset of cells that regulate the development of humoral immunity by promoting the production of antibody-producing plasma cells and long-lived memory B cells. Classically, TFH cells are identified by the high expression of CXCR5 associated with high IL-21 production. However, environmental and genetic conditions may impact the functional status of these cells. Thus, the objective of this thesis was to study circulating TFH cells (cTFH) in immunologically differentiated individuals as pregnant, infected or not with HIV-1, and patients with common variable immunodeficiency (CVID). In this context, our results showed that pregnancy in healthy women favors the expansion of CD45RO+CXCR5+CD4+ T cells, coexpressing or not the CXCR3, PD-1 and ICOS markers. In addition, pregnancy also increased the percentage of IL-21, IL-10 and IL-6 producing CXCR3+ cTFH cells. Interestingly, a positive correlation was observed between the percentage of CXCR3+PD-1+ cTFH cells, as well as the IL-21+ subtype, with serum estrogen levels and anti-cytomegalovirus (CMV) and anti-hepatitis B virus (HBs) antibodies. Therefore, pregnancy should affect the function of cTFH cells in adverse situations, such as in HIV-1 infection. As expected, viral infection reduced the frequency of different subsets of cTFH cells, however, pregnancy increased the ability of antiretroviral therapy (ARV) to improve the functional recovery of these lymphocytes determined by the ability to produce IL-21 and to assist autologous B cells to produce IgG in co-culture systems. Additionally, an increase in the percentage of IL-21+ cTFH cells after ARV was directly correlated to estrogen levels and to anti-HBsAg and anti-tetanus toxoid (TT) IgG titers. In addition to acquired immunodeficiencies, some primary immunodeficiencies compromise the production of antibodies, which may be associated with changes in cTFH cells. Our results showed a reduction in the percentage of cTFH17 cells in patients with CVID and an increase in the ratio of TFH/follicular regulatory T cells (TFR) cells only in patients with autoimmune disease. Moreover, the percentage of IL-21 producing cTFH cells was directly related to the percentage of CD27+ IgD- B cells in patients with CVID. Cocultures with cTFH and memory B cells showed that some patients with CVID were able to produce antibody levels similar to the control group while others do not. However, cTFH cells from patients who did not produce immunoglobulins in vitro were able to assist B cells from control individuals to produce antibodies, suggesting an intrinsic B cell defect to produce or secrete immunoglobulins.