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Unconventional Pro-inflammatory CD4+ T Cell Response in B Cell-Deficient Mice Infected with Trypanosoma cruzi
Melisa Gorosito Serrán1, Jimena Tosello Boari1, Facundo Fiocca Vernengo1
1Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI - CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
Insights
B cells, particularly plasmablasts/plasma cells, are crucial for regulating T cell responses during Trypanosoma cruzi infection. Their absence in mice led to increased TNF-producing CD4+ T cells, uncontrolled inflammation, and higher mortality in Chagas disease.
Area of Science:
- Immunology
- Parasitology
- Infectious Diseases
Background:
- Chagas disease, caused by Trypanosoma cruzi, is a growing global health issue.
- Parasite persistence and immune response intensity influence Chagas disease severity.
- Dysregulated inflammation can lead to tissue damage and organ dysfunction.
Purpose of the Study:
- To investigate the role of B cells in modulating T cell responses during Trypanosoma cruzi infection.
- To understand how B cell deficiency impacts the immune landscape and disease progression.
Main Methods:
- Utilized B cell-deficient mice (muMT mice) and specific B cell-deficient mice (Blimp-flox/flox-CD23icre).
- Infected mice with Trypanosoma cruzi and analyzed immune cell populations (CD4+ T cells, B cells) and cytokine production (TNF, IFNγ).
- Conducted CD4+ T cell transfer experiments to assess functional impacts.
Main Results:
- B cell-deficient mice showed increased TNF-producing CD4+ T cells, elevated plasma TNF, and higher mortality.
- Absence of B cells led to reduced IFNγ+ CD4+ T cells and decreased regulatory T cell populations (Foxp3+, IL-10+, IL17+).
- Plasmablast/plasma cells appear to regulate TNF-producing CD4+ T cells, as their absence exacerbated inflammation.
Conclusions:
- B cells significantly influence T cell responses in Trypanosoma cruzi infection.
- The absence of B cells promotes an uncontrolled CD4+ T cell effector response and inflammation.
- Plasmablasts/plasma cells may play a regulatory role in mitigating excessive inflammation during Chagas disease.
Abstract:
Chagas disease, caused by the parasite Trypanosoma cruzi, is endemic in Latin America but has become a global public health concern by migration of infected people. It has been reported that parasite persistence as well as the intensity of the inflammatory immune response are determinants of the clinical manifestations of the disease. Even though inflammation is indispensable for host defense, when deregulated, it can contribute to tissue injury and organ dysfunction. Here, we report the importance of B cells in conditioning T cell response in T. cruzi infection. Mice deficient in mature B cells (muMT mice) infected with T. cruzi exhibited an increase in plasma TNF concentration, TNF-producing CD4+ T cells, and mortality. The increase in TNF-producing CD4+ T cells was accompanied by a reduction in IFNγ+CD4+ T cells and a decrease of the frequency of regulatory Foxp3+, IL-10+, and IL17+CD4+ T cells populations. The CD4+ T cell population activated by T. cruzi infection, in absence of mature B cells, had a high frequency of Ly6C+ cells and showed a lower expression of inhibitory molecules such as CTLA-4, PD-1, and LAG3. CD4+ T cells from infected muMT mice presented a high frequency of CD62LhiCD44- cells, which is commonly associated with a naïve phenotype. Through transfer experiments we demonstrated that CD4+ T cells from infected muMT mice were able to condition the CD4+ T cells response from infected wild-type mice. Interestingly, using Blimp-flox/flox-CD23icre mice we observed that in absence of plasmablast/plasma cell T. cruzi-infected mice exhibited a higher number of TNF-producing CD4+ T cells. Our results showed that the absence of B cells during T. cruzi infection affected the T cell response at different levels and generated a favorable scenario for unconventional activation of CD4+ T cell leading to an uncontrolled effector response and inflammation. The product of B cell differentiation, the plasmablast/plasma cells, could be able to regulate TNF-producing CD4+ T cells since their absence favor the increase of the number of TNF+ CD4+ in T. cruzi-infected mice.
