RESUMO
The precursors of TCRαß+CD8αα+ intraepithelial lymphocytes (IEL) arise in the thymus through a complex process of agonist selection. We and others have shown that the proapoptotic protein, Bim, is critical to limit the number of thymic IEL precursors (IELp), as loss of Bim at the CD4+CD8+ double-positive stage of development drastically increases IELp. The factors determining this cell death versus survival decision remain largely unknown. In this study, we used CD4CreBcl2f/f mice to define the role of the antiapoptotic protein Bcl-2 and CD4CreBcl2f/fBimf/f mice to determine the role of Bcl-2 in opposing Bim to promote survival of IELp. First, in wild-type mice, we defined distinct subpopulations within PD-1+CD122+ IELp, based on their expression of Runx3 and α4ß7. Coexpression of α4ß7 and Runx3 marked IELp that were most dependent upon Bcl-2 for survival. Importantly, the additional loss of Bim restored Runx3+α4ß7+ IELp, showing that Bcl-2 antagonizes Bim to enable IELp survival. Further, the loss of thymic IELp in CD4CreBcl2f/f mice also led to a dramatic loss of IEL in the gut, and the additional loss of Bim restored gut IEL. The loss of gut IEL was due to both reduced seeding by IELp from the thymus as well as a requirement for Bcl-2 for peripheral IEL survival. Together, these findings highlight subset-specific and temporal roles for Bcl-2 in driving the survival of TCRαß+CD8αα+ IEL and thymic IELp.
Assuntos
Proteína 11 Semelhante a Bcl-2/metabolismo , Linfócitos Intraepiteliais/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Timo/citologia , Animais , Antígenos CD4/metabolismo , Antígenos CD8/metabolismo , Sobrevivência Celular/imunologia , Subunidade alfa 3 de Fator de Ligação ao Core/metabolismo , Feminino , Linfócitos Intraepiteliais/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Células-Tronco/citologia , Timo/imunologiaRESUMO
T cells play a critical role in immune responses as they specifically recognize peptide/MHC complexes with their T-cell receptors and initiate adaptive immune responses. While T cells are critical for performing appropriate effector functions and maintaining immune memory, they also can cause autoimmunity or neoplasia if misdirected or dysregulated. Thus, T cells must be tightly regulated from their development onward. Maintenance of appropriate T-cell homeostasis is essential to promote protective immunity and limit autoimmunity and neoplasia. This review will focus on the role of cell death in maintenance of T-cell homeostasis and outline novel therapeutic strategies tailored to manipulate cell death to limit T-cell survival (eg, autoimmunity and transplantation) or enhance T-cell survival (eg, vaccination and immune deficiency).
Assuntos
Doenças Autoimunes/imunologia , Rejeição de Enxerto/imunologia , Síndromes de Imunodeficiência/imunologia , Imunoterapia/métodos , Linfócitos T/fisiologia , Animais , Doenças Autoimunes/terapia , Morte Celular , Sobrevivência Celular , Rejeição de Enxerto/prevenção & controle , Homeostase , Humanos , Síndromes de Imunodeficiência/terapia , Transplante , VacinaçãoRESUMO
BACKGROUND & AIMS: CD1d-restricted natural killer (NK) T cells are a subset of immunoregulatory T cells that comprise type I (express the semi-invariant T-cell receptor [TCR] and can be detected using the α-galactosylceramide/CD1d tetramer) and type II (express diverse TCRs and cannot be directly identified). Studies in mouse models of inflammatory bowel disease revealed a complex role for type I NKT cells in the development of colitis. Type II NKT cells have been associated with intestinal inflammation in patients with ulcerative colitis. METHODS: To investigate whether dysregulation of type II NKT cells, caused by increased expression of CD1d, can contribute to colitis, we generated transgenic mice that express high levels of CD1d and a TCR from an autoreactive, type II NKT cell (CD1dTg/24αßTg mice). RESULTS: CD1dTg/24αßTg mice had reduced numbers of 24αß T cells compared with 24αßTg mice, indicating that negative selection increases among type II NKT cells engaged by abundant self-antigen. The residual 24αß T cells in CD1dTg/24αßTg mice had an altered surface phenotype and acquired a cytokine profile distinct from that of equivalent cells in 24αßTg mice. Interestingly, CD1dTg/24αßTg mice spontaneously developed colitis; adoptive transfer experiments confirmed that type II NKT cells that develop in the context of increased CD1d expression are pathogenic. CONCLUSIONS: Aberrant type II NKT cell responses directly contribute to intestinal inflammation in mice, indicating the importance of CD1d expression levels in the development and regulation of type II NKT cells.
Assuntos
Antígenos CD1d/metabolismo , Colite Ulcerativa/imunologia , Células T Matadoras Naturais/metabolismo , Animais , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Citometria de Fluxo , Camundongos , Camundongos TransgênicosRESUMO
Following their proliferative expansion and differentiation into effector cells like Th1, Tfh, and T central memory precursors (Tcmp), most effector CD4+ T cells die, while some survive and become memory cells. Here, we explored how Bcl-2 family members controlled the survival of CD4+ T cells during distinct phases of mouse acute LCMV infection. During expansion, we found that Th1 cells dominated the response, downregulated expression of Bcl-2, and did not require Bcl-2 for survival. Instead, they relied on the anti-apoptotic protein, A1 for survival. Similarly, Th17 cells in an EAE model also depended on A1 for survival. However, after the peak of the response, CD4+ effector T cells required Bcl-2 to counteract Bim to aid their transition into memory. This Bcl-2 dependence persisted in established memory CD4+ T cells. Combined, these data show a temporal switch in Bcl-2 family-mediated survival of CD4+ T cells over the course of an immune response. This knowledge can help improve T cell survival to boost immunity and conversely, target pathogenic T cells.
RESUMO
Although the human nonclassical class Ib major histocompatibility complex (Mhc) locus, HLA-G, is known to act as an immune suppressor in immune-privileged sites, little is currently known regarding participation of the rodent class Ib Mhc in similar pathways. Here, we investigated the expression properties of the mouse nonclassical Mhc H2-Q5(k) gene, previously detected in tumors and tissues associated with pregnancy. We find that H2-Q5(k) is alternatively spliced into multiple novel isoforms in a wide panel of C3H tissues. Unlike other known class I MHC, it is most highly transcribed in the brain, where the classical class Ia Mhc products are scarce. The truncated isoforms are selectively enriched in sites of immune privilege and are translated into cell surface proteins in neural crest-derived transfected cells. Furthermore, we present data supporting a model whereby Q5(k) isoforms serve an immune-protective role by donating their Qdm leader peptide to Qa-1, in a pathway homologous to the HLA-G leader fragment binding HLA-E and inhibiting CD94/NKG2A-positive cytotoxic cells. In addition, we report a previously unknown homolog of H2-Q5(k) in the C57BL/6 mouse, which encodes Qdm, but is transcribed solely into noncanonical isoforms. Collectively, these studies demonstrate that H2-Q5(k), and its homologous class I-like H2(b) gene may play tissue-specific roles in regulating immune surveillance.
Assuntos
Encéfalo/imunologia , Encéfalo/metabolismo , Antígenos H-2/genética , Antígenos H-2/metabolismo , Peptídeos/genética , Peptídeos/imunologia , Processamento Alternativo , Sequência de Aminoácidos , Animais , Sequência de Bases , Primers do DNA/genética , Feminino , Genes MHC Classe I , Humanos , Masculino , Camundongos , Camundongos Endogâmicos AKR , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Peptídeos/metabolismo , Gravidez , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Isoformas de Proteínas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Distribuição TecidualRESUMO
Most effector CD8+ T cells die, while some persist and become either "effector" (TEM) or "central" (TCM) memory T cells. Paradoxically, effector CD8+ T cells with greater memory potential have higher levels of the pro-apoptotic molecule Bim. Here, we report, using a novel Bim-mCherry knock-in mouse, that cells with high levels of Bim preferentially develop into TCM cells. Bim levels remained stable and were regulated by DNA methylation at the Bim promoter. Notably, high levels of Bcl-2 were required for Bimhi cells to survive. Using Nur77-GFP mice as an indicator of TCR signal strength, Nur77 levels correlated with Bim expression and Nur77hi cells also selectively developed into TCM cells. Altogether, these data show that Bim levels and TCR signal strength are predictive of TEM- vs. TCM-cell fate. Further, given the many other biologic functions of Bim, these mice will have broad utility beyond CD8+ T-cell fate.