Journal Article

Co-transplantation of pure blood stem cells with antigen-specific but not bulk T cells augments functional immunity

Brown, Janice M, Shizuru, Judith A, Florek, Mareike, Kohrt, Holbrook E. K, Küpper, Natascha J, Negrin, Robert S, Müller, Antonia M. S, Shashidhar, Sumana

2012

Overview

Impaired immunity is a fundamental obstacle to successful allogeneic hematopoietic cell transplantation. Mature graft T cells are thought to provide protection from infections early after transplantation, but can cause life-threatening graft-vs.-host disease. Human CMV is a major pathogen after transplantation. We studied reactivity against the mouse homologue, murine CMV (MCMV), in lethally irradiated mice given allogeneic purified hematopoietic stem cells (HSCs) or HSCs supplemented with T cells or T-cell subsets. Unexpectedly, recipients of purified HSCs mounted superior antiviral responses compared with recipients of HSC plus unselected bulk T cells. Furthermore, supplementation of purified HSC grafts with CD8+ memory or MCMV-specific T cells resulted in enhanced antiviral reactivity. Posttransplantation lymphopenia promoted massive expansion of MCMV-specific T cells when no competing donor T cells were present. In recipients of pure HSCs, naive and memory T cells and innate lymphoid cell populations developed. In contrast, the lymphoid pool in recipients of bulk T cells was dominated by effector memory cells. These studies show that pure HSC transplantations allow superior protective immunity against a viral pathogen compared with unselected mature T cells. This reductionist transplant model reveals the impact of graft composition on regeneration of host, newly generated, and mature transferred T cells, and underscores the deleterious effects of bulk donor T cells. Our findings lead us to conclude that grafts composed of purified HSCs provide an optimal platform for in vivo expansion of selected antigen-specific cells while allowing the reconstitution of a naive T-cell pool.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Animal models / Animals / Antivirals / Biological Sciences / Blood / CD8 antigen / CD8-Positive T-Lymphocytes / CD8-Positive T-Lymphocytes - immunology / Cell Differentiation / Cell Proliferation / cell transplantation / cytology / Disease Models, Animal / Effector cells / Epitopes / Epitopes - immunology / Hematocrit / Hematopoietic Stem Cell Transplantation / Hematopoietic Stem Cells / Hematopoietic Stem Cells - cytology / Hematopoietic Stem Cells - metabolism / Hemopoiesis / Herpesviridae Infections / Herpesviridae Infections - immunology / Human cytomegalovirus / Humans / immunity / Immunity - immunology / Immunization / Immunological memory / immunology / Infection / Lymph nodes / Lymphocyte Subsets / Lymphocyte Subsets - immunology / Lymphocytes / Lymphocytes T / Lymphoid cells / Lymphoid tissue / Lymphopenia / Lymphopenia - immunology / Memory cells / metabolism / Mice / Mice, Inbred BALB C / Mice, Inbred C57BL / Murine cytomegalovirus / Muromegalovirus / Pathogens / Rodents / Spleen / Stem cells / Supplementation / T cell receptors / T lymphocytes / T-Lymphocytes - cytology / T-Lymphocytes - transplantation / Tissue grafting / Transplantation / Transplants & implants / Virus Activation / Virus Activation - immunology