RESUMO
The IL-17 family contributes to host defense against many intracellular pathogens by mechanisms that are not fully understood. CD8+ T lymphocytes are key elements against intracellular microbes, and their survival and ability to mount cytotoxic responses are orchestrated by several cytokines. Here, we demonstrated that IL-17RA-signaling cytokines sustain pathogen-specific CD8+ T cell immunity. The absence of IL-17RA and IL-17A/F during Trypanosoma cruzi infection resulted in increased tissue parasitism and reduced frequency of parasite-specific CD8+ T cells. Impaired IL-17RA-signaling in vivo increased apoptosis of parasite-specific CD8+ T cells, while in vitro recombinant IL-17 down-regulated the pro-apoptotic protein BAD and promoted the survival of activated CD8+ T cells. Phenotypic, functional, and transcriptomic profiling showed that T. cruzi-specific CD8+ T cells derived from IL-17RA-deficient mice presented features of cell dysfunction. PD-L1 blockade partially restored the magnitude of CD8+ T cell responses and parasite control in these mice. Adoptive transfer experiments established that IL-17RA-signaling is intrinsically required for the proper maintenance of functional effector CD8+ T cells. Altogether, our results identify IL-17RA and IL-17A as critical factors for sustaining CD8+ T cell immunity to T. cruzi.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Doença de Chagas/imunologia , Doença de Chagas/metabolismo , Receptores de Interleucina-17/metabolismo , Transdução de Sinais , Trypanosoma cruzi/imunologia , Transferência Adotiva , Animais , Apoptose , Sobrevivência Celular , Doença de Chagas/microbiologia , Citocinas/metabolismo , Feminino , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Imunomodulação/genética , Interleucina-17/metabolismo , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Masculino , Camundongos , Camundongos Knockout , Receptores de Interleucina-17/deficiência , Transcrição GênicaRESUMO
Here we identified B cells as a major source of rapid, innate-like production of interleukin 17 (IL-17) in vivo in response to infection with Trypanosoma cruzi. IL-17(+) B cells had a plasmablast phenotype, outnumbered cells of the TH17 subset of helper T cells and were required for an optimal response to this pathogen. With both mouse and human primary B cells, we found that exposure to parasite-derived trans-sialidase in vitro was sufficient to trigger modification of the cell-surface mucin CD45, which led to signaling dependent on the kinase Btk and production of IL-17A or IL-17F via a transcriptional program independent of the transcription factors RORγt and Ahr. Our combined data suggest that the generation of IL-17(+) B cells may be a previously unappreciated feature of innate immune responses required for pathogen control or IL-17-mediated autoimmunity.
Assuntos
Linfócitos B/imunologia , Doença de Chagas/imunologia , Glicoproteínas/metabolismo , Interleucina-17/imunologia , Neuraminidase/metabolismo , Trypanosoma cruzi/enzimologia , Trypanosoma cruzi/imunologia , Animais , Linfócitos B/parasitologia , Proliferação de Células , Células Cultivadas , Doença de Chagas/genética , Glicoproteínas/genética , Humanos , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neuraminidase/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/parasitologia , Células Th17/imunologia , Células Th17/parasitologia , Ativação Transcricional/imunologiaRESUMO
B1 cells produce most natural Abs in unimmunized mice and play a key role in the response to thymus-independent Ags and microbial infection. Enlargement of B1 cell number in mice is often associated with autoimmunity. However, the factors that control peripheral B1 cell survival remain poorly characterized. Mice lacking the inhibitory receptor FcγRIIb exhibit a massive expansion in peritoneal B1 cells, implicating this receptor in B1 cell homeostasis. In this study, we show that peritoneal B1 cells express the highest levels of FcγRIIb among B cell subsets and are highly susceptible to FcγRIIb-mediated apoptosis. B1 cells upregulate FcγRIIb in response to innate signals, including CpG, and the B cell homeostatic cytokine BAFF efficiently protects activated B1 cells from FcγRIIb-mediated apoptosis via receptor downregulation. BAFF-transgenic mice manifest an expansion of peritoneal B1 cells that express lower levels of FcγRIIb and exhibit reduced susceptibility to apoptosis. Whereas both peritoneal B1 cells from wild-type and BAFF-transgenic mice immunized with CpG exhibit an increase in FcγRIIb levels, this change is blunted in BAFF-transgenic animals. Our combined results demonstrate that FcγRIIb controls peritoneal B1 cell survival and this program can be modulated by the BAFF signaling axis.
Assuntos
Fator Ativador de Células B/fisiologia , Subpopulações de Linfócitos B/citologia , Subpopulações de Linfócitos B/imunologia , Receptores de IgG/fisiologia , Animais , Apoptose/genética , Apoptose/imunologia , Fator Ativador de Células B/biossíntese , Fator Ativador de Células B/deficiência , Subpopulações de Linfócitos B/metabolismo , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Células Cultivadas , Predisposição Genética para Doença/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Camundongos Transgênicos , Cavidade Peritoneal/citologia , Receptores de IgG/biossíntese , Receptores de IgG/deficiência , Transdução de Sinais/genética , Transdução de Sinais/imunologiaRESUMO
In this review, we discuss how protozoan parasites alter immature and mature B cell compartment. B1 and marginal zone (MZ) B cells, considered innate like B cells, are activated during protozoan parasite infections, and they generate short lived plasma cells providing a prompt antibody source. In addition, protozoan infections induce massive B cell response with polyclonal activation that leads to hypergammaglobulnemia with serum antibodies specific for the parasites and self and/or non related antigens. To protect themselves, the parasites have evolved unique ways to evade B cell immune responses inducing apoptosis of MZ and conventional mature B cells. As a consequence of the parasite induced-apoptosis, the early IgM response and an already establish humoral immunity are affected during the protozoan parasite infection. Moreover, some trypanosomatides trigger bone marrow immature B cell apoptosis, influencing the generation of new mature B cells. Simultaneously with their ability to release antibodies, B cells produce cytokines/quemokines that influence the characteristic of cellular immune response and consequently the progression of parasite infections.
RESUMO
Acute infection with Trypanosoma cruzi, the aetiological agent of Chagas' disease, results in parasitaemia and polyclonal lymphocyte activation. It has been reported that polyclonal B-cell activation is associated with hypergammaglobulinaemia and delayed parasite-specific antibody response. In the present study we analysed the development of a B-cell response within the different microenvironments of the spleen during acute T. cruzi infection. We observed massive germinal centre (GC) and extrafollicular (EF) responses at the peak of infection. However, the EF foci were evident since day 3 post-infection (p.i.), and, early in the infection, they mainly provided IgM. The EF foci response reached its peak at 11 days p.i. and extended from the red pulp into the periarteriolar lymphatic sheath. The GCs were detected from day 8 p.i. At the peak of parasitaemia, CD138(+) B220(+) plasma cells in EF foci, red pulp and T-cell zone expressed IgM and all the IgG isotypes. Instead of the substantial B-cell response, most of the antibodies produced by splenic cells did not target the parasite, and parasite-specific IgG isotypes could be detected in sera only after 18 days p.i. We also observed that the bone marrow of infected mice presented a strong reduction in CD138(+) B220(+) cells compared with that of normal mice. Hence, in acute infection with T. cruzi, the spleen appears to be the most important lymphoid organ that lodges plasma cells and the main producer of antibodies. The development of a B-cell response during T. cruzi infection shows features that are particular to T. cruzi and other protozoan infection but different to other infections or immunization with model antigens.
Assuntos
Anticorpos/imunologia , Linfócitos B/imunologia , Baço/citologia , Baço/imunologia , Trypanosoma cruzi/imunologia , Animais , Anticorpos Antiprotozoários/imunologia , Doença de Chagas/imunologia , Doença de Chagas/parasitologia , Contagem de Linfócitos , Camundongos , Camundongos Endogâmicos BALB C , Trypanosoma cruzi/isolamento & purificaçãoRESUMO
BACKGROUND: B cells and antibodies are involved not only in controlling the spread of blood circulating Trypanosoma cruzi, but also in the autoreactive manifestations observed in Chagas disease. Acute infection results in polyclonal B cell activation associated with hypergammaglobulinemia, delayed specific humoral immunity and high levels of non-parasite specific antibodies. Since TNF superfamily B lymphocyte Stimulator (BAFF) mediates polyclonal B cell response in vitro triggered by T. cruzi antigens, and BAFF-Tg mice show similar signs to T. cruzi infected mice, we hypothesized that BAFF can mediate polyclonal B cell response in experimental Chagas disease. METHODOLOGY/PRINCIPAL FINDINGS: BAFF is produced early and persists throughout the infection. To analyze BAFF role in experimental Chagas disease, Balb/c infected mice were injected with BR3:Fc, a soluble receptor of BAFF, to block BAFF activity. By BAFF blockade we observed that this cytokine mediates the mature B cell response and the production of non-parasite specific IgM and IgG. BAFF also influences the development of antinuclear IgG and parasite-specific IgM response, not affecting T. cruzi-specific IgG and parasitemia. Interestingly, BAFF inhibition favors the parasitism in heart. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate, for the first time, an active role for BAFF in shaping the mature B cell repertoire in a parasite infection.
Assuntos
Anticorpos Antiprotozoários/biossíntese , Fator Ativador de Células B/metabolismo , Linfócitos B/imunologia , Doença de Chagas/imunologia , Baço/imunologia , Trypanosoma cruzi/imunologia , Animais , Fator Ativador de Células B/antagonistas & inibidores , Modelos Animais de Doenças , Imunoglobulina G/biossíntese , Imunoglobulina M/biossíntese , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Humoral immunity during experimental Chagas disease has been considered a double-edge sword, critical to control Trypanosoma cruzi spreading but also associated to tissue damage. Peritoneal B-1 cells have been linked to the pathogenesis of Chagas disease; however, they may also help to control the infection by providing a fast wave of antibodies. In the present work, we determined that peritoneal B-cell response to T. cruzi is characterized by a marked reduction of CD19(+) B cells due to plasma cell differentiation rather than to cell death. Both peritoneal B-2 and B-1 cells decrease after parasite infection, but with different kinetics. Thus, the reduction in B-2 cell number can be detected from day 4 postinfection while the number of B-1 cells decreases only after 15 days of infection. Differentiation of peritoneal B-1 and B-2 cells into IgM-secreting cells was triggered by parasites but not by cytokines produced by peritoneal cells. Electron microscopy studies showed that peritoneum of infected mice lodges plasma cells with typical morphology as well as atypical plasma cells named 'Mott-like cells' containing high number of cytoplasmatic Ig(+) granules. The plasma cells induced during the infection showed a phenotype that may allow their persistence in peritoneum and they may contribute to the high levels of antibodies exhibited at the chronic phase of infection. We also showed that the peritoneal B-cell response is scarcely specific for the invading pathogen and rather constitute an important source of non-parasite-specific IgM and IgG in the infected host.