Prolactin Increases the Frequency of Follicular T Helper Cells with Enhanced IL21 Secretion and OX40 Expression in Lupus-Prone MRL/lpr Mice

Abstract

Systemic lupus erythematosus is characterized by high levels of IgG class autoantibodies that contribute to the pathophysiology of the disease. The formation of these autoantibodies occurs in the germinal centers, where there is cooperation between follicular T helper cells (TFH) and autoreactive B cells. Prolactin has been reported to exacerbate the clinical manifestations of lupus by increasing autoantibody concentrations. The objective of this study was to characterize the participation of prolactin in the differentiation and activation of TFH cells, by performing in vivo and in vitro tests with lupus-prone mice, using flow cytometry and real-time PCR. We found that TFH cells express the long isoform of the prolactin receptor and promoted STAT3 phosphorylation. Receptor expression was higher in MRL/lpr mice and correlative with the manifestations of the disease. Although prolactin does not intervene in the differentiation of TFH cells, it does favor their activation by increasing the percentage of TFH OX40+ and TFH IL21+ cells, as well as leading to high serum concentrations of IL21. These results support a mechanism in which prolactin participates in the emergence of lupus by inducing overactive TFH cells and perhaps promoting dysfunctional germinal centers.

Prolactin promotes proliferation of germinal center B cells, formation of plasma cells, and elevated levels of IgG3 anti-dsDNA autoantibodies

“…PRL does not seem to affect the formation of mature FO and MZ B cells, since we did not find differences in the absolute numbers of these populations ( 16 ). However, in T cells PRL increases the expression of CD25 and CD69 (activation molecules) on T cells ( 40 , 41 ), and of OX40 on follicular T cells ( 42 ). We did not observe an effect of PRL on the expression of the B-cell activation markers CD80 and CD86.…”

The effect of prolactin on immune cell subsets involved in SLE pathogenesis

“…have reported that PRL increased the number and activation of IL21-producing OX40+ Tfh cells. These cells promoted the formation of GCs, interfered with tolerance induction, and facilitated the generation of autoreactive plasma cells, with the consequent autoantibody secretion ( 52 ). In SLE patients, a higher percentage of CD4+ OX40+ T cells has also been shown to indicate increased disease activity ( 53 ) ( Figure 1 ).…”

Señalización del receptor de prolactina en linfocitos T foliculares y B de centro germinal en ratones MRL/lpr

“…En nuestro grupo de trabajo, se ha tratado de comprender el papel de la PRL en el desarrollo del LES utilizando ratones MRL/lpr. Se ha demostrado de manera ex vivo que los linfocitos B-GC y Tfh expresan la isoforma larga del R-PRL tanto en las cepas que desarrollan LES como en la cepa control (C57BL/6) (Alemán-García et al, 2021;Carreon, 2019). En los linfocitos Tfh de los ratones que desarrollan LES la expresión del receptor es mayor e incrementa conforme a la edad, presentando un patrón diferente con respecto a la cepa control.…”

“…En los linfocitos Tfh de los ratones que desarrollan LES la expresión del receptor es mayor e incrementa conforme a la edad, presentando un patrón diferente con respecto a la cepa control. (Alemán-García et al, 2021).…”