Invariant NKT Cells Promote the Development of Highly Cytotoxic Multipotent CXCR3+CCR4+CD8+ T Cells That Mediate Rapid Hepatocyte Allograft Rejection

Abstract The ability of CD8+ T cells to engage a diverse range of peptide–major histocompatibility complex (MHC) complexes can also lead to cross-recognition of self and nonself peptide-MHC complexes and thus directly contribute toward allograft rejection or autoimmunity. Here we present a novel form of cross-recognition by herpes virus–specific CD8+ cytotoxic T cells that challenges the current paradigm of self/non-self recognition. Functional characterization of a human leukocyte antigen (HLA) Cw*0602-restricted cytomegalovirus-specific CD8+ T-cell response revealed an unusual dual specificity toward a pp65 epitope and the alloantigen HLA DR4. This cross-recognition of HLA DR4 alloantigen was critically dependent on the coexpression of HLA DM and was preferentially directed toward the B-cell lineage. Furthermore, allostimulation of peripheral blood lymphocytes with HLA DRB*0401-expressing cells rapidly expanded CD8+ T cells, which recognized the pp65 epitope in the context of HLA Cw*0602. T-cell repertoire analysis revealed 2 dominant populations expressing T-cell receptor beta variable (TRBV)4-3 or TRBV13, with cross-reactivity exclusively mediated by the TRBV13+ clonotypes. More importantly, cross-reactive TRBV13+ clonotypes displayed markedly lower T-cell receptor binding affinity and a distinct pattern of peptide recognition, presumably mimicking a structure presented on the HLA DR4 allotype. These results illustrate a novel mechanism whereby virus-specific CD8+ T cells can cross-recognize HLA class II molecules and may contribute toward allograft rejection and/or autoimmunity.

Download Full-text

The Presence of HLA-E-Restricted, CMV-Specific CD8+ T Cells in the Blood of Lung Transplant Recipients Correlates with Chronic Allograft Rejection

PLoS ONE ◽

10.1371/journal.pone.0135972 ◽

2015 ◽

Vol 10 (8) ◽

pp. e0135972 ◽

Cited By ~ 9

Author(s):

Lucy C. Sullivan ◽

Glen P. Westall ◽

Jacqueline M. L. Widjaja ◽

Nicole A. Mifsud ◽

Thi H. O. Nguyen ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Allograft Rejection ◽

Lung Transplant ◽

Transplant Recipients ◽

Chronic Allograft Rejection ◽

Lung Transplant Recipients

Download Full-text

Characterization of NK1.1+ CD8 T Cells in Allogeneic Hematopoietic Cell Transplantation Recipients

Blood ◽

10.1182/blood.v112.11.4616.4616 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4616-4616

Author(s):

Yi Wang ◽

Hui Wang ◽

Shumei Wang ◽

Megan Sykes ◽

Yong-Guang Yang

Keyword(s):

Bone Marrow ◽

T Cells ◽

Cell Transplantation ◽

Cd8 T Cells ◽

Hematopoietic Cell Transplantation ◽

Flow Cytometric Analysis ◽

Nkt Cells ◽

Hematopoietic Cell ◽

Allogeneic Hematopoietic Cell Transplantation ◽

Memory Phenotype

Abstract NKT cells from naïve mice are mainly CD4+ or CD4−CD8−. However, it has been reported that CD8+ NKT cells can be expanded in vitro from splenocytes, bone marrow cells and thymocytes of C57BL/6 (B6) mice by stimulation with anti-CD3 mAb and cytokines, and that the expanded CD8+ NKT cells mediate strong graft-vs.-leukemic (GVL) effects without severe GVHD after adoptive transfer into allogeneic mice. We now describe the presence of CD8+NK1.1+ cells in recipient livers (approximately 2–6%), but not in other tissues (spleen, lung, bone marrow, thymus and PBMC), in various allogeneic hematopoietic cell transplantation (allo-HCT) models. The generation of CD8+NK1.1+ cells is likely a consequence of alloresponses, as these cells were not detected in the liver of syngeneic HCT controls. Flow cytometric analysis confirmed that these cells are CD1d-independent, TCRαβ+ T cells with a memory phenotype (CD44+ and CD62L−), and do not express CD49b, Ly-49C/I, Ly-49G2, or Ly-49D. In a sublethally (6 Gy)-irradiated B6-to-B6D2F1 allo-HCT model, NK1.1+ CD8 T cells became detectable by week 2, increased in number until approximately week 8, and gradually declined thereafter but were still detectable in the liver at day 100 after allo-HCT. By using CD45.1 and CD45.2 congeneic donors, we determined that the majority of NK1.1+ CD8 T cells were derived from the donor splenocytes. Furthermore, depletion of CD8+, but not NK1.1+, cells from the donor splenocytes prior to transplantation prevented the generation of NK1.1+ CD8 T cells, indicating that these cells were derived from donor NK1.1−CD8+ splenic T cells. Our data demonstrate that donor CD8 T cells can acquire NK1.1 expression upon activation in allo-HCT recipients, and that these NK1.1+ CD8 T cells maintain a memory phenotype and persist in the recipients with preferential accumulation in the liver. Studies are currently in progress to determine the role of activated donor NK1.1+ CD8 T cells in GVHD and GVL effects.

Download Full-text