CD4 + CD8 + T-Lymphocytes in Xenogeneic and Human Graft-versus-Host Disease

• Published in: Frontiers in immunology Vol. 11; p. 579776
• Main Authors: Alhaj Hussen, Kutaiba, Michonneau, David, Biajoux, Vincent, Keita, Seydou, Dubouchet, Laetitia, Nelson, Elisabeth, Setterblad, Niclas, Le Buanec, Helene, Bouaziz, Jean-David, Guimiot, Fabien, Socié, Gérard, Canque, Bruno
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers 24-11-2020; Frontiers Media S.A
• Subjects: allogeneic hematopoietic stem cell transplantation; Animals; CD4+CD8+ T lymphocytes; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cytokines; Female; Graft vs Host Disease; graft-versus-host disease; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Memory; Immunology; immunoregulatory diversion; Life Sciences; Male; Mice; Mice, SCID; Programmed Cell Death 1 Receptor; T-Lymphocytes, Cytotoxic; Transplantation, Heterologous; xenograft mouse model; immunoregulatory diversion; xenograft mouse model; graft-versus-host disease; CD4+CD8+ T lymphocytes; allogeneic hematopoietic stem cell transplantation; CD4 + CD8 + T lymphocytes
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2020.579776

Mechanisms driving acute graft-versus-host disease (aGVHD) onset in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) are still poorly understood. To provide a detailed characterization of tissue-infiltrating T lymphocytes (TL) and search for eventual site-specific specificities, we developed a xenogeneic model of aGVHD in immunodeficient mice. Phenotypic characterization of xenoreactive T lymphocytes (TL) in diseased mice disclosed a massive infiltration of GVHD target organs by an original CD4
CD8
TL subset. Immunophenotypic and transcriptional profiling shows that CD4
CD8
TL comprise a major PD1
CD62L
transitional memory subset (>60%) characterized by low level expression of cytotoxicity-related transcripts. CD4
CD8
TL produce high IL-10 and IL-13 levels, and low IL-2 and IFN-γ, suggestive of regulatory function. In vivo tracking of genetically labeled CD4
or CD8
TL subsequently found that CD4
CD8
TL mainly originate from chronically activated cytotoxic TL (CTL). On the other hand, phenotypic profiling of CD3
TL from blood, duodenum or rectal mucosa in a cohort of allo-HSCT patients failed to disclose abnormal expansion of CD4
CD8
TL independent of aGVHD development. Collectively, our results show that acquisition of surface CD4 by xenoreactive CD8
CTL is associated with functional diversion toward a regulatory phenotype, but rule out a central role of this subset in the pathogenesis of aGVHD in allo-HSCT patients.