Trypanosoma cruzi Induces B Cells That Regulate the CD4+ T Cell Response.

Martín Somoza,Adriano Bertelli,Oscar Campetella,Juan Mucci,Ramiro E Verdun,Cecilia A Pratto

doi:10.3389/fcimb.2021.789373

Abstract

Trypanosoma cruzi infection induces a polyclonal B cell proliferative response characterized by maturation to plasma cells, excessive generation of germinal centers, and secretion of parasite-unrelated antibodies. Although traditionally reduced to the humoral response, several infectious and non-infectious models revealed that B lymphocytes could regulate and play crucial roles in cellular responses. Here, we analyze the trypomastigote-induced effect on B cells, their effects on CD4+ T cells, and their correlation with in vivo findings. The trypomastigotes were able to induce the proliferation and the production of IL-10 or IL-6 of naïve B cells in co-culture experiments. Also, we found that IL-10-producing B220lo cells were elicited in vivo. We also found up-regulated expression of FasL and PD-L1, proteins involved in apoptosis induction and inhibition of TCR signaling, and of BAFF and APRIL mRNAs, two B-cell growth factors. Interestingly, it was observed that IL-21, which plays a critical role in regulatory B cell differentiation, was significantly increased in B220+/IL-21+ in in vivo infections. This is striking since the secretion of IL-21 is associated with T helper follicular cells. Furthermore, trypomastigote-stimulated B-cell conditioned medium dramatically reduced the proliferation and increased the apoptotic rate on CD3/CD28 activated CD4+ T cells, suggesting the development of effective regulatory B cells. In this condition, CD4+ T cells showed a marked decrease in proliferation and viability with marginal IL-2 or IFNγ secretion, which is counterproductive with an efficient immune response against T. cruzi. Altogether, our results show that B lymphocytes stimulated with trypomastigotes adopt a particular phenotype that exerts a strong regulation of this T cell compartment by inducing apoptosis, arresting cell division, and affecting the developing of a proinflammatory response.

Highlights

B cells are the main effectors of the humoral immunity, which is mediated by their activation and secretion of different classes of immunoglobulins against the original antigen (Nutt et al, 2015) these cells exhibit other antibody-independent functions such as their performance as antigen-presenting-cell (APC) or cytokine secretion that modulate the entire immune response (Shen and Fillatreau, 2015; Getahun and Cambier, 2019).The immune response associated with survival against infection by Trypanosoma cruzi, the agent of Chagas disease, infection relies on the generation of a CD4+ T helper 1 (Th1) profile and a strong CD8+ T response that is, unable to resolve the infection (Tarleton et al, 2000; Kumar and Tarleton, 2001)
It has been observed in vivo that unspecific B cells proliferate during T. cruzi infection, which could be considered to occur in a T-dependent and/or in a T-independent manner (D’Imperio Lima et al, 1985; Minoprio et al, 1987)
We found that the B cell proliferation was strikingly enhanced when the agonist anti-CD40 antibody was added to the culture to mimic the presence of CD40L (Figure 1B)

Summary

Introduction

B cells are the main effectors of the humoral immunity, which is mediated by their activation and secretion of different classes of immunoglobulins against the original antigen (Nutt et al, 2015) these cells exhibit other antibody-independent functions such as their performance as antigen-presenting-cell (APC) or cytokine secretion that modulate the entire immune response (Shen and Fillatreau, 2015; Getahun and Cambier, 2019).The immune response associated with survival against infection by Trypanosoma cruzi, the agent of Chagas disease, infection relies on the generation of a CD4+ T helper 1 (Th1) profile and a strong CD8+ T response that is, unable to resolve the infection (Tarleton et al, 2000; Kumar and Tarleton, 2001). T. cruzi induces polyclonal lymphocytes proliferation and unspecific hypergammaglobulinemia during the early stage of the acute phase of the infection with an antigen-specific delayed response (Ortiz-Ortiz et al, 1980; Minoprio et al, 1988; Rottenberg et al, 1993; el Bouhdidi et al, 1994; Bermejo et al, 2011). This unspecific antibody response is characterized by their maturation as plasma cells and the secretion of parasiteunrelated antibodies, a response that is maintained all along the infectious process (D’Imperio Lima et al, 1986; Minoprio et al, 1988; Bermejo et al, 2011).

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Conclusion