Estudo da biologia das células T auxiliares foliculares circulantes em condições imunológicas distintas: gestação, infecção pelo HIV-1 e em pacientes com desordens do espectro da neuromielite óptica

Abstract

Follicular helper T (TFH) cells are a subtype of lymphocytes responsible for regulating the development of humoral immunity by promoting the induction of antibody-secreting plasma cells and long-term memory B cells. Classically, TFH cells are identified by the high expression of CXCR5 associated with an elevated production of IL-21. However, different environmental and genetic conditions can interfere with the functional status of these cells. Thus, the general objective of this thesis was to study the biology of circulating TFH cells in pregnant women, infected or not with HIV-1, and in women with a definitive diagnosis of NMOSD.Additionally, we also evaluated the mechanisms of effect of pregnancy-related dose of estrogen and progesterone on the functional status of these lymphocytes. In this context, our results showed that pregnancy, in healthy women, favors the expansion of CD45RO+CXCR5+CD4+ T cells, coexpressing or not CXCR3, PD-1 and ICOS markers. In addition, pregnancy also increased the percentage of CXCR3+ TFH cells that produce IL-21, IL-10 and IL-6. Interestingly, a positive correlation was observed between the percentage of CXCR3+ PD-1+ TFH cells, as well as IL-21+ subtype, with serum levels of both estrogen and IgG directed against cytomegalovirus and hepatitis B virus (HBsAg). In HIV-1-infected women, the occurrence of pregnancy accelerated the numerical and functional recovery of circulating TFH cells after the introduction of antiretroviral therapy (ART), amplifying their ability to assist autologous B cells to produce IgG in coculture systems. Additionally, an increase in the percentage of IL-21+ TFH cells after ART was directly correlated with plasma estrogen levels and anti-HBs and anti-tetanus toxoid (TT) IgG titers. When we evaluated the direct effect of gestational hormones on the in vitro TFH cells, estrogen increased the percentage of cTFH, ICOS+cTFH, IL-21+ and IL-17+ cTFH, and memory B cells, while progesterone, with along estrogen, increased not only the proportion of antibody-secreting plasma cells, but also the percentage of IL-10+TFR cells, a cell subtype known to prevent autoantibody production in humoral autoimmune diseases, such as NMOSD. In this sense, our results showed that NMOSD patients who produce anti-AQP4 IgG had a higher frequency of IL-6+ and IL-17+TFH cells, which were directly correlated with the clinical activity of the disease, as well as a lower percentage of cells IL-10+TFH. In summary, our results suggest that high levels of estrogen and progesterone favor the expansion and differentiation of functional TFH cells, which may be linked to a better specific humoral response against pathogens, but it can negatively impact the outcome of autoimmune diseases mediated by autoantibodies, such as NMOSD.