ABSTRACT
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.
Subject(s)
CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/immunology , Immunologic Memory/immunology , Lymphocyte Activation/immunology , Receptors, Immunologic/metabolism , Animals , Basic-Leucine Zipper Transcription Factors/genetics , Cell Differentiation/immunology , Cell Line, Tumor , Cell Lineage/immunology , Influenza A virus/immunology , Interleukin-12 Subunit p35/immunology , Lectins, C-Type , Listeria monocytogenes/immunology , Melanoma, Experimental , Mice , Mice, Inbred C57BL , Mice, Knockout , Receptors, Immunologic/genetics , Vesicular stomatitis Indiana virus/immunologyABSTRACT
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.
Subject(s)
Killer Cells, Natural/immunology , Animals , CD8-Positive T-Lymphocytes/immunology , Disease Models, Animal , Humans , Immunity, Innate/immunology , Interleukin Receptor Common gamma Subunit/immunology , Interleukin-15/immunology , Lymphocytes/immunology , Mice , Mice, SCID , Receptors, Immunologic/immunology , Rituximab/immunologyABSTRACT
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.