RESUMEN
CD8 T cell memory offers critical antiviral protection, even in the absence of neutralizing antibodies. The paradigm is that CD8 T cell memory within the lung tissue consists of a mix of circulating TEM cells and non-circulating TRM cells. However, based on our analysis, the heterogeneity within the tissue is much higher, identifying TCM, TEM, TRM, and a multitude of populations which do not perfectly fit these classifications. Further interrogation of the populations shows that TRM cells that express CD49a, both with and without CD103, have increased and diverse effector potential compared with CD49a negative populations. These populations function as a one-man band, displaying antiviral activity, chemokine production, release of GM-CSF, and the ability to kill specific targets in vitro with delayed kinetics compared with effector CD8 T cells. Together, this study establishes that CD49a defines multiple polyfunctional CD8 memory subsets after clearance of influenza infection, which act to eliminate virus in the absence of direct killing, recruit and mature innate immune cells, and destroy infected cells if the virus persists.
Asunto(s)
Alphainfluenzavirus/inmunología , Linfocitos T CD8-positivos/metabolismo , Memoria Inmunológica , Integrina alfa1/metabolismo , Pulmón/metabolismo , Células T de Memoria/metabolismo , Infecciones por Orthomyxoviridae/metabolismo , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/virología , Células Cultivadas , Quimiocinas/metabolismo , Citotoxicidad Inmunológica , Modelos Animales de Enfermedad , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Interacciones Huésped-Patógeno , Alphainfluenzavirus/patogenicidad , Cinética , Pulmón/inmunología , Pulmón/virología , Masculino , Células T de Memoria/inmunología , Células T de Memoria/virología , Ratones Endogámicos C57BL , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/virología , FenotipoRESUMEN
Tissue resident memory (TRM) CD8 T cells comprise a memory population that forms in peripheral, non-lymphoid tissues after an infection that does not recirculate into the bloodstream or other tissues. TRM cells often recognize conserved peptide epitopes shared among different strains of a pathogen and so offer a protective role upon secondary encounter with the same or related pathogens. Several recent studies have begun to shed light on the intrinsic and extrinsic factors regulating TRM. In addition, work is being done to understand how canonical "markers" of TRM actually affect the function of these cells. Many of these markers regulate the generation or persistence of these TRM cells, an important point of study due to the differences in persistence of TRM between tissues, which may impact future vaccine development to cater towards these important differences. In this review, we will discuss recent advances in TRM biology that may lead to strategies designed to promote this important protective immune subset.
RESUMEN
INK4A/ARF mutations are acquired in bcr/abl(+) lymphoid blast phase chronic myelogenous leukemia (CML) and bcr/abl(+) acute lymphoblastic leukemia (ALL). Donor lymphocyte infusion and graft-versus-leukemia (GVL) are generally ineffective in such ALLs, whereas GVL is highly active against bcr/abl(+) CML, which does not have a lesion in the INK4A/ARF locus. The mechanisms for the ineffectiveness of GVL are not fully known, and it is possible that intrinsic resistance of acute lymphoid leukemias to immune effectors associated with allogeneic GVL may contribute to ineffectiveness. This work tested the hypothesis that INK4A/ARF mutations that are associated with transformation of bcr/abl(+) CML to an ALL phenotype, and that are associated with increased resistance to apoptosis render ALL cells insensitive to allogeneic immune responses to minor histocompatibility antigens (mHA). Murine acute pre-B ALLs were induced by transfer of the human p210 bcr/abl gene into bone marrow of INK4A/ARF null mice. These ALL lines were then studied in a murine model of MHC-matched, mHA-mismatched allogeneic BMT. In vivo growth of these ALLs was inhibited in allogeneic transplants characterized by active allogeneic immune responses compared to their behavior in syngeneic transplants. In vitro ALLs with INK4A/ARF, p210 bcr/abl, or p190 bcr/abl mutations remained sensitive to anti-mHA cytolytic T cells. In addition, the ALLs were capable of inducing primary immune responses to mHAs in vivo. Thus, ALLs with INK4A/ARF or bcr/abl mutations are not intrinsically resistant to allogeneic T cell responses, suggesting that active immunotherapies against mHA have the potential to control such acute lymphoblastic leukemias.
Asunto(s)
Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Proteínas de Fusión bcr-abl/genética , Efecto Injerto vs Leucemia/inmunología , Antígenos de Histocompatibilidad Menor/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Citotóxicos/inmunología , Animales , Apoptosis/inmunología , Trasplante de Médula Ósea , Células Cultivadas/inmunología , Inhibidor p16 de la Quinasa Dependiente de Ciclina/deficiencia , Progresión de la Enfermedad , Genes abl , Genes p16 , Humanos , Células Asesinas Naturales/inmunología , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Inmunológicos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/cirugía , Quimera por Radiación , Subgrupos de Linfocitos T/trasplante , Linfocitos T Citotóxicos/trasplante , Trasplante Homólogo/inmunologíaRESUMEN
The immune environment present after allogeneic hematopoietic stem cell transplantation (HSCT) contributes to the control of leukemia. Our laboratory has demonstrated in a murine model that vaccination of recipients after transplantation with recipient tumor vaccines does not exacerbate graft-versus-host disease but does induce meaningful graft-versus-tumor effects. We previously demonstrated that part of the reason for the lack of graft-versus-host disease from post-transplantation vaccination is due to gradual acquisition of tolerance or unresponsiveness to recipient immunodominant minor histocompatibility antigens that are ubiquitously expressed in the recipient. However, our prior studies have not critically addressed the question of whether a similar process of acquisition of unresponsiveness to or tolerance of antigens present on minimal residual disease also occurs. The present study tested the hypothesis that unresponsiveness to antigens present on minimal residual disease present at the time of HSCT would also occur. The answer to this question would have a significant effect on the potential efficacy of post-transplantation tumor vaccines. In a murine model of major histocompatibility complex matched, minor histocompatibility antigen mismatched HSCT (C3.SW female donors and C57BL/6 female recipients), we tested whether transplant recipients would acquire unresponsiveness to antigens present on small numbers of residual leukemia/lymphoma cells. We employed a male C57BL/6 lymphoid malignancy with an immunoglobulin/c-myc oncogene in these studies using as a model of tumor-restricted antigen the well-characterized male (HY) antigen system present only on the tumor but not present as ubiquitous minor antigens in the recipient. After HSCT, recipients did not mount immune responses to the ubiquitously distributed immunodominant recipient strain H7 minor histocompatibility antigen, but did retain the capacity to mount significant T cell responses to HY antigens present on small numbers of HY+ tumor cells present at transplantation. Additional studies using small numbers of nonmalignant recipient male B cells or dendritic cells as models of minimal residual disease also demonstrated that the transplant recipients retained their capacity to mount anti-HY T cell responses. After HSCT, recipients may retain the capacity to mount effective T cell responses to antigens present on minimal residual disease and still acquire relative tolerance to ubiquitously distributed immunodominant minor antigens that are related to graft-versus-host disease.