Self-reactive memory-phenotype CD8 T cells exhibit both MHC-restricted and non-MHC-restricted cytotoxicity: a role for the T-cell receptor and natural killer cell receptors

Dhanji, Salim; Teh, Soo-Jeet; Oble, Darryl A.; Priatel, John J.; Teh, Hung‐Sia

doi:10.1182/blood-2004-01-0150

Cited by 35 publications

(51 citation statements)

References 37 publications

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“…Their less vigorous negative selection that was observed in ITK Ϫ/Ϫ mice may explain their involvement in autoimmune reactions (25). A similar cell type was described in cultures that use high concentrations of IL-2 or IL-15 (26,27). Similar to our results, these cultured cells responded to cells that expressed NK receptor ligands.…”

Section: Resultssupporting

confidence: 79%

ITK and IL-15 support two distinct subsets of CD8⁺T cells

Dubois

Waldmann

Müller

2006

Proc. Natl. Acad. Sci. U.S.A.

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(3,4). In addition, IL-15 Ϫ/Ϫ mice are unable to maintain antigen-specific CD8 ϩ memory T cells after immunization with viruses (5, 6). These defects point to functions of IL-15 in both adaptive and innate immunity.Antigenic stimulation of naïve CD8 ϩ T cells induces the high expression of CD44 (7,8), for which all CD44 hi CD8 ϩ T cells were termed ''memory phenotype'' cells. An injection of IL-15 into mice induces the expansion of these CD8 ϩ CD44 hi T cells independent of antigenic stimulation (9, 10). It was concluded that IL-15 directly supports the maintenance of CD8 ϩ memory T cells. However, a number of other treatments also selectively increase the number of CD8 ϩ CD44 hi T cells without antigenic stimulation that include ''bystander'' proliferation in response to poly I:C or LPS (11), proliferation after an injection of mature dendritic cells (12), or lymphopenia-induced proliferation after CD8 ϩ T cell transfer into irradiated hosts (13,14). Because the presence of antigen should be a necessity for the generation of true memory cells, subsets of CD8 ϩ CD44 hi T cells may have functions other than in CD8 memory.Mice with a deletion in the tec kinase ITK have reduced numbers of both peripheral CD4 ϩ and CD8 ϩ T cells (15). Among the CD8 ϩ T cells that are present, the majority express high levels of CD44 and CD122 (16). The function of these cells has not been fully elucidated. Defects in CD8 ϩ T cells in ITK Ϫ/Ϫ mice include positive and negative selection, cytokine production, TCR engagement-induced proliferation, and reduced cytolytic activity against allogenic splenocytes and against virally infected cells (15).Here we show that IL-15 and ITK support two distinct subsets of CD8 ϩ T cells that are present in both the thymus and the periphery. The two subpopulations of CD8 ϩ T cells appear to have independent functions in the periphery. ResultsCD8 ؉ T Cells in ITK ؊/؊ Mice Depend on IL-15. CD8 ϩ T cells in ITK Ϫ/Ϫ mice and in IL-15 Ϫ/Ϫ mice are phenotypically different. In particular, CD8 ϩ T cells in ITK Ϫ/Ϫ mice express high levels of CD44 and CD122. In contrast, IL-15 Ϫ/Ϫ CD8 ϩ T cells express low levels of CD44 and CD122. This difference could be caused by a dysregulation of both surface markers. Alternatively, ITK and IL-15 could support two distinct subsets of CD8 ϩ T cells. To distinguish between these possibilities, we determined whether the CD44 hi CD122 hi CD8 ϩ T cells in ITK Ϫ/Ϫ mice depend on IL-15. We initially injected the antibody ⌻m␤1, which inhibits the activity of transpresented IL-15 on the IL-2͞15R␤ chain. One week after a 50-g injection of ⌻m␤1, the percentage of peripheral blood CD8 ϩ T cells in ITK Ϫ/Ϫ mice was reduced to Ͻ15% compared with untreated wild-type mice (Fig. 1A). All of the remaining CD8 ϩ T cells expressed high levels of CD44 and CD122 ( Fig. 1 A and data not shown).We then generated mice that are deficient in both ITK and IL-15. CD8 ϩ CD44 hi CD122 hi T cells represent 10-30% of all CD8 ϩ T cells in young wild-type mice. As described previously (3) and as shown i...

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Section: Resultssupporting

confidence: 79%

ITK and IL-15 support two distinct subsets of CD8⁺T cells

Dubois

Waldmann

Müller

2006

Proc. Natl. Acad. Sci. U.S.A.

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“…After IL-2 stimulation, they up-regulate NK cell markers in addition to NKG2D, and they express DAP12. Furthermore, in male H-Y TCR-transgenic mice, in which the majority of thymocytes are negatively selected due to expression of the male Ag, lymphocytes of similar phenotype and functionality can be found in the periphery (21). These cells also express DAP12, and their cytolytic function can be activated directly by NKG2D.…”

Section: Cd44mentioning

confidence: 99%

“…Instead, a small subpopulation of mouse CD8 ϩ T cells is apparently able to proliferate in response to inflammatory cytokines, such as IL-2 and IL-15, leading to the acquisition of NKG2D activity. This activity might be due to the expression of DAP12 in these cells (20,21), because it has previously been demonstrated that activated T cells can be directly stimulated through NKG2D, if DAP12 expression is enforced as a transgene in mouse T cells (18).…”

Section: Cd44mentioning

confidence: 99%

Engagement of NKG2D by Cognate Ligand or Antibody Alone Is Insufficient to Mediate Costimulation of Human and Mouse CD8+ T Cells

Ehrlich

Ogasawara

Hamerman

et al. 2005

The Journal of Immunology

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CD8+ T cells require a signal through a costimulatory receptor in addition to TCR engagement to become activated. The role of CD28 in costimulating T cell activation is well established. NKG2D, a receptor found on NK cells, CD8+ αβ-TCR+ T cells, and γδ-TCR+ T cells, has also been implicated in T cell costimulation. In this study we have evaluated the role of NKG2D in costimulating mouse and human naive and effector CD8+ T cells. Unexpectedly, in contrast to CD28, NKG2D engagement by ligand or mAb is not sufficient to costimulate naive or effector CD8+ T cell responses in conventional T cell populations. While NKG2D did not costimulate CD8+ T cells on its own, it was able to modify CD28-mediated costimulation of human CD8+ T cells under certain contitions. It is, therefore, likely that NKG2D acts as a costimulatory molecule only under restricted conditions or requires additional cofactors.

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“…NKG2D, a C-type lectin-like activating receptor, is expressed on several immune cells including NK 2 Although it remains unclear whether NKG2D can directly activate ␣␤ and/or ␥␦ T cells, NKG2D indeed enhances the antigendependent activation of T cells and provides both activating and co-stimulatory signals in NK cells (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13), suggesting that it plays important roles in both innate and adaptive immune responses. ULBPs belong to a recently identified ligand family for NKG2D in humans.…”

mentioning

confidence: 99%

RAET1E2, a Soluble Isoform of the UL16-binding Protein RAET1E Produced by Tumor Cells, Inhibits NKG2D-mediated NK Cytotoxicity

Cao

Zhang

et al. 2007

Journal of Biological Chemistry

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UL16-binding proteins (ULBPs 14 -21). ULBP gene family consists of 10 members, six of which encode potentially functional glycoproteins that are located near the tip of its long arm at q24.2-q25.3, close to the human equivalent of the mouse H2-linked t-complex. This subchromosomal region is similar to a segment of mouse chromosome 10 harboring the orthologous MHC class I-related retinoic acid early transcript loci, Raet1a-d (22). Among them, ULBP1, ULBP2, ULBP3, and RAET1L are linked to membrane through a glycosylphosphatidylinositol anchor, whereas RAET1E and RAET1G contain transmembrane and cytoplasmic domains.By engaging the NKG2D activating receptor, ULBPs can directly activate NK cells to proliferate and secrete cytokines. Co-stimulation of NK cells with ULBPs and interleukin-12 greatly enhances the production of multiple cytokines and chemokines (17). In addition, in vitro, some target cells insensitive to NK cells can be efficiently lysed when transfected with ULBPs (14,19,21). In vivo, the expression of ULBPs correlates with improved survival in cancer patients, and ectopic expression of ULBPs on murine EL4 or RMA tumor cells elicits potent anti-tumor responses in syngeneic C57BL/6 and severe combined immunodeficiency disease mice, which can be strongly enhanced by interleukin-15 (20). Accordingly, Andreas Diefenbach et al. (23) demonstrated the efficacy of using NKG2D ligands as components of vaccine, which may offer new approaches for malignancies. Moreover, it was shown that DNA-based vaccines encoding syngeneic or allogeneic NKG2D ligands together with tumor antigens could markedly activate both innate and adaptive anti-tumor immunity (24,25

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Self-reactive memory-phenotype CD8 T cells exhibit both MHC-restricted and non-MHC-restricted cytotoxicity: a role for the T-cell receptor and natural killer cell receptors

Cited by 35 publications

References 37 publications

ITK and IL-15 support two distinct subsets of CD8⁺T cells

ITK and IL-15 support two distinct subsets of CD8⁺T cells

Engagement of NKG2D by Cognate Ligand or Antibody Alone Is Insufficient to Mediate Costimulation of Human and Mouse CD8+ T Cells

RAET1E2, a Soluble Isoform of the UL16-binding Protein RAET1E Produced by Tumor Cells, Inhibits NKG2D-mediated NK Cytotoxicity

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Self-reactive memory-phenotype CD8 T cells exhibit both MHC-restricted and non-MHC-restricted cytotoxicity: a role for the T-cell receptor and natural killer cell receptors

Cited by 35 publications

References 37 publications

ITK and IL-15 support two distinct subsets of CD8+T cells

ITK and IL-15 support two distinct subsets of CD8+T cells

Engagement of NKG2D by Cognate Ligand or Antibody Alone Is Insufficient to Mediate Costimulation of Human and Mouse CD8+ T Cells

RAET1E2, a Soluble Isoform of the UL16-binding Protein RAET1E Produced by Tumor Cells, Inhibits NKG2D-mediated NK Cytotoxicity

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ITK and IL-15 support two distinct subsets of CD8⁺T cells

ITK and IL-15 support two distinct subsets of CD8⁺T cells