RESUMO
Mouse models have been instrumental in establishing fundamental principles of cancer initiation and progression and continue to be invaluable in the discovery and further development of cancer therapies. Nevertheless, important aspects of human disease are imperfectly approximated in mouse models, notably the involvement of endogenous retroviruses (ERVs). Replication-defective ERVs, present in both humans and mice, may affect tumor development and antitumor immunity through mechanisms not involving infection. Here, we revealed an adverse effect of murine ERVs with restored infectivity on the behavior of mouse cancer models. In contrast to human cancer, where infectious ERVs have never been detected, we found that ERV infectivity was frequently restored in transplantable, as well as genetic, mouse cancer models. Such replication-competent, ERV-derived retroviruses were responsible for unusually high expression of retroviral nucleic acids and proteins in mouse cancers. Infectious ERV-derived retroviruses produced by mouse cancer cells could directly infect tumor-infiltrating host immune cells and fundamentally modified the host's immune defenses to cancer, as well as the outcome of immunotherapy. Therefore, infectious retroviruses, variably arising in mouse cancer models, but not in human cancer, have the potential to confound many immunologic studies and should be considered as a variable, if not altogether avoided. Cancer Immunol Res; 6(11); 1292-300. ©2018 AACR.
Assuntos
Retrovirus Endógenos/patogenicidade , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/virologia , Animais , Linhagem Celular Tumoral , Feminino , Vírus da Leucemia Murina/genética , Vírus da Leucemia Murina/patogenicidade , Linfócitos do Interstício Tumoral/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Transgênicos , Neoplasias Experimentais/patologia , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Proteínas Proto-Oncogênicas B-raf/genética , Infecções por Retroviridae/virologia , Tropismo Viral/fisiologiaRESUMO
CD4+ follicular helper T (Tfh) cells have been shown to be critical for the activation of germinal center (GC) B-cell responses. Similar to other infections, Plasmodium infection activates both GC as well as non-GC B cell responses. Here, we sought to explore whether Tfh cells and GC B cells are required to eliminate a Plasmodium infection. A CD4 T cell-targeted deletion of the gene that encodes Bcl6, the master transcription factor for the Tfh program, resulted in complete disruption of the Tfh response to Plasmodium chabaudi in C57BL/6 mice and consequent disruption of GC responses and IgG responses and the inability to eliminate the otherwise self-resolving chronic P. chabaudi infection. On the other hand, and contrary to previous observations in immunization and viral infection models, Signaling Lymphocyte Activation Molecule (SLAM)-Associated Protein (SAP)-deficient mice were able to activate Tfh cells, GC B cells, and IgG responses to the parasite. This study demonstrates the critical role for Tfh cells in controlling this systemic infection, and highlights differences in the signals required to activate GC B cell responses to this complex parasite compared with those of protein immunizations and viral infections. Therefore, these data are highly pertinent for designing malaria vaccines able to activate broadly protective B-cell responses.
Assuntos
Células Dendríticas Foliculares/imunologia , Malária/imunologia , Plasmodium chabaudi/imunologia , Proteínas Proto-Oncogênicas c-bcl-6/genética , Animais , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular , Deleção de Genes , Imunoglobulina G/metabolismo , Ativação Linfocitária , Malária/genética , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Auxiliares-IndutoresRESUMO
Elucidation of the immune requirements for control or elimination of retroviral infection remains an important aim. We studied the induction of adaptive immunity to neonatal infection with a murine retrovirus, under conditions leading to immunological tolerance. We found that the absence of either maternal or offspring adaptive immunity permitted efficient vertical transmission of the retrovirus. Maternal immunodeficiency allowed the retrovirus to induce central Th cell tolerance in the infected offspring. In turn, this compromised the offspring's ability to mount a protective Th cell-dependent B cell response. However, in contrast to T cells, offspring B cells were not centrally tolerized and retained their ability to respond to the infection when provided with T cell help. Thus, escape of retrovirus-specific B cells from deletional tolerance offers the opportunity to induce protective retroviral immunity by restoration of retrovirus-specific T cell help, suggesting similar T cell immunotherapies for persistent viral infections.
Assuntos
Transferência Adotiva , Linfócitos B/imunologia , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Vírus da Leucemia Murina/imunologia , Leucemia Experimental/prevenção & controle , Infecções por Retroviridae/prevenção & controle , Linfócitos T/imunologia , Infecções Tumorais por Vírus/prevenção & controle , Animais , Animais Recém-Nascidos , Linfócitos B/transplante , Linfócitos B/virologia , Células Cultivadas , Tolerância Central , Feminino , Leucemia Experimental/imunologia , Masculino , Exposição Materna/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Gravidez , Infecções por Retroviridae/imunologia , Infecções por Retroviridae/transmissão , Linfócitos T/transplante , Linfócitos T/virologia , Infecções Tumorais por Vírus/imunologia , Infecções Tumorais por Vírus/transmissãoRESUMO
Protection against malaria in humans can be achieved by repeated exposure to infected mosquito bites during prophylactic chloroquine treatment (chemoprophylaxis and sporozoites (CPS)). We established a new mouse model of CPS immunization to investigate the stage and strain-specificity of malaria immunity. Immunization with Plasmodium chabaudi by mosquito bite under chloroquine cover does not generate pre-erythrocytic immunity, which is acquired only after immunization with high sporozoite doses. Instead, CPS immunization by bite elicits long-lived protection against blood-stage parasites. Blood-stage immunity is effective against a virulent, genetically distinct strain of P. chabaudi. Importantly, if exposure to blood-stage parasitemia is extended, blood-stage parasites induce cross-stage immunity targeting pre-erythrocytic stages. We therefore show that CPS immunization can induce robust, long-lived heterologous blood-stage immunity, in addition to protection against pre-erythrocytic parasites following high dose sporozoite immunization. Cross-stage immunity elicited by blood-stage parasites may further enhance efficacy of this immunization regimen.