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Infection of several mouse strains with Trypanosoma cruzi stimulates high levels of T and B lymphocyte activities which persist during the chronic phase and is followed by specific immunosuppression and severe autoimmune pathology. Infected BALB.Xid mice carrying an X-linked mutation and lacking CD5 B cells, display poor B cell responses to T. cruzi infection, accompanied by low levels of specific and non-specific immunoglobulins in the serum. However, these animals control parasitemia, do not show the wasting observed in BALB/c mice, and develop almost no pathology early in the chronic phase. The infection of (BALB.Xid female x BALB/c male) F1 animals shows that immunodefective males behave like Xid animals in contrast to females which respond as normal BALB/c mice. These results indicate that the Xid locus controls lymphocyte responses, parasite clearance and pathology in experimental Chagas' disease.

In our study we describe further characteristics of a CD4+ T cell line (G-05) isolated from lymph nodes of C3H/HeJ mice chronically infected with Trypanosoma cruzi. This T cell line secreted lymphokines such as interleukin (IL) 4 and IL 5 and could be defined as a TH2 type of helper T cells. By passive transfer into naive mice, the G-05 line was able to induce a polyclonal B cell activation in the spleen. This splenic B cell activation was quite similar to that seen in chronically T. cruzi-infected animals, where the isotypic pattern presents a large increase of IgG2a and IgG2b isotypes. Moreover, it was possible to reproduce this kind of polyclonal B cell activation in vivo, with the supernatant of G-05 T cells cultured in the presence of T. cruzi extract, accessory cells and exogenous IL 2. Analysis of this supernatant showed the presence of large amounts of IL 4, IL 5, IL 3 and IL 6 but not of interferon-gamma, and residual IL 2 activity was not significant. These results suggest that the G-05 T cells considered as TH2 cells on the basis of their lymphokine production are involved in the development of the in vivo polyclonal B cell activation in T. cruzi infection.

Cytotoxic treatment of BALB/c cells from different peripheral lymphoid tissues by a cocktail of monoclonal antibodies against Thy-1, Ly-1, L3T4 and Ly-2 differentiation markers (anti-T cocktail) plus complement eliminates all mature T lymphocytes. Yet a population of dull Thy-1+, Ly-1-, L3T4-, Ly-2-, corresponding to about 1% of the initial population, can be detected by flow cytometry which proliferate under concanavalin A stimulation. These anti-T killing-resistant cells (TKR) were previously shown to be capable of differentiating in culture into class II-restricted autoreactive T helper cells. We demonstrate here that such cells can be detected in mice of BALB/c and DBA/2 genetic background but are absent in C57BL/6 and B10 animals. The presence of TKR cells is dominant in (BALB/c x C57BL/6)F1 hybrids and genetically controlled by two genes which are neither H-2 nor Igh linked. TKR cells are also detected in young NZB mice but disappear with the development of the systemic autoimmune disease in old animals. Thy-1+, L3T4-, Ly-2- cells from MRL lpr/lpr mice also respond to concanavalin A but are removed by the anti-T treatment. Altogether, arguments are presented suggesting that TKR cells represent a particular subset of double-negative peripheral T cells which may correspond to autoreactive T cell recursors that would escape the thymic selection. We postulate that these cells are present in all mouse strains but their susceptibility to killing by anti-Thy-1 antibodies differs depending on background genes.

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A new population of dull Thy-1+, Ly-1-, Lyt-2-, L3T4- PNA- cells, resistant to a double cytotoxic treatment by monoclonal antibodies to these T cell markers plus complement, has been isolated from the spleen of normal adult BALB/c and DBA/2 mice (Tkr cells). These cells exhibit no spontaneous autoreactivity or alloreactivity but can be activated with concanavalin A (Con A). Once activated, they differentiate into bright Thy-1+, Ly-1+, Lyt-2-, L3T4+ PNA- T lymphocytes. Con A-activated Tkr cells also strongly proliferate in the presence of allogeneic or syngeneic dendritic cells in secondary cultures. Moreover, contrary to other Con A-stimulated T cell populations, they induce B lymphocytes to proliferate and to differentiate into Ig-secreting cells at a very high level. Con A-activated Tkr cells are therefore very potent polyclonal B cell activators. Restimulated of Tkr cells by syngeneic dendritic cells can be inhibited by anti-L3T4 or anti-class II monoclonal antibodies. The results suggest that Tkr cells are the precursors of class II-specific autoreactive T helper cells. Tkr cells are absent in the spleen of B6 animals. This indicates that their expression might be genetically controlled. It also suggests that Tkr cells may not be the unique splenic precursors of autoreactive T cells. Con A activation of Tkr cells in Click's medium is 2-mercaptoethanol dependent and highly sensitive to pCO2, like the response of thymocytes. Tkr cells are also absent in the spleen of nude mice. We conclude that Tkr cells represent splenic precursors of autoreactive T helper cells equivalent to Thy-1+, Ly-2-, L3T4- PNA- cortical thymocytes.

The effects of infections with Plasmodium chabaudi or Trypanosoma cruzi on chronic CD8+ T cell dependent IgG2ab suppression were analyzed in homozygous Ighb/b adult mice. These parasites are known to induce a CD4+ T cell dependent polyclonal activation characterized in particular by a considerable increase in IgG2a expression. We report here that infection with either parasite reversed the IgG2ab suppression in 18 out of 32 mice. However, in mice treated with anti-CD4 mAb in parallel to the parasite infection, the polyclonal activation was largely reduced and the suppression of IgG2ab expression was always maintained. The parasite induced escape from suppression could result from increased helper T cell activation stimulating some of the Ig production. A weakening of the CD8+ T cell activity which is specific of IgG2ab could also contribute to the IgG2ab production. Both effects would shift the previous equilibrium which was in favour of suppression to a new balance allowing expression of the IgG2ab allotype.