RESUMEN
Protective immunity against pathogens depends on the efficient generation of functionally diverse effector and memory T lymphocytes. However, whether plasticity during effector-to-memory CD8+ T cell differentiation affects memory lineage specification and functional versatility remains unclear. Using genetic fate mapping analysis of highly cytotoxic KLRG1+ effector CD8+ T cells, we demonstrated that KLRG1+ cells receiving intermediate amounts of activating and inflammatory signals downregulated KLRG1 during the contraction phase in a Bach2-dependent manner and differentiated into all memory T cell linages, including CX3CR1int peripheral memory cells and tissue-resident memory cells. "ExKLRG1" memory cells retained high cytotoxic and proliferative capacity distinct from other populations, which contributed to effective anti-influenza and anti-tumor immunity. Our work demonstrates that developmental plasticity of KLRG1+ effector CD8+ T cells is important in promoting functionally versatile memory cells and long-term protective immunity.
Asunto(s)
Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Memoria Inmunológica/inmunología , Activación de Linfocitos/inmunología , Receptores Inmunológicos/metabolismo , Animales , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Diferenciación Celular/inmunología , Línea Celular Tumoral , Linaje de la Célula/inmunología , Virus de la Influenza A/inmunología , Subunidad p35 de la Interleucina-12/inmunología , Lectinas Tipo C , Listeria monocytogenes/inmunología , Melanoma Experimental , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores Inmunológicos/genética , Virus de la Estomatitis Vesicular Indiana/inmunologíaRESUMEN
Immunodeficient mice reconstituted with a human immune system represent a promising tool for translational research as they may allow modeling and therapy of human diseases in vivo. However, insufficient development and function of human natural killer (NK) cells and T cell subsets limit the applicability of humanized mice for studying cancer biology and therapy. Here, we describe a human interleukin 15 (IL15) and human signal regulatory protein alpha (SIRPA) knock-in mouse on a Rag2-/- Il2rg-/- background (SRG-15). Transplantation of human hematopoietic stem and progenitor cells into SRG-15 mice dramatically improved the development and functional maturation of circulating and tissue-resident human NK and CD8+ T cells and promoted the development of tissue-resident innate lymphoid cell (ILC) subsets. Profiling of human NK cell subsets by mass cytometry revealed a highly similar expression pattern of killer inhibitory receptors and other candidate molecules in NK cell subpopulations between SRG-15 mice and humans. In contrast to nonobese diabetic severe combined immunodeficient Il2rg-/- (NSG) mice, human NK cells in SRG-15 mice did not require preactivation but infiltrated a Burkitt's lymphoma xenograft and efficiently inhibited tumor growth following treatment with the therapeutic antibody rituximab. Our humanized mouse model may thus be useful for preclinical testing of novel human NK cell-targeted and combinatory cancer immunotherapies and for studying how they elicit human antitumor immune responses in vivo.
Asunto(s)
Células Asesinas Naturales/inmunología , Animales , Linfocitos T CD8-positivos/inmunología , Modelos Animales de Enfermedad , Humanos , Inmunidad Innata/inmunología , Subunidad gamma Común de Receptores de Interleucina/inmunología , Interleucina-15/inmunología , Linfocitos/inmunología , Ratones , Ratones SCID , Receptores Inmunológicos/inmunología , Rituximab/inmunologíaRESUMEN
Despite scientific evidence supporting the fact that vaccines are fundamental tools for preventing infectious diseases, a percentage of the population still refuses some or all of them. Vaccine hesitancy has become a widespread issue, and its complexity lies in the great variety of factors that can influence decisions about immunization, which are not just vaccine-related concerns, but also involve personal and societal levels. Our research group performed an extensive literature review to analyze: (1) different age groups, their relation to the problem and their characteristics; (2) the most important information (key messages) about immunization that could be used to counteract hesitancy; and (3) best approaches to transmit the messages to the target groups. We propose a long-term approach to overcome vaccine hesitancy that involves the education of children and adolescents on the basics about immunization and critical thinking, using different communication channels.