Human peripheral blood (PB) contains a unique CD8+ T cell subpopulation expressing natural killer (NK) cell receptors, CD94 and CD161 that are called NKT cells. Although CD28 is a critical costimulatory molecule for the initial activation of naïve T cells, it has limited activity for NKT cells. Thus, alternate molecules responsible for costimulating or maintaining CD8+ NKT cells need to be defined. In this study, we present evidence suggesting that 4-1BB (CDwl37), known to promote CD8+ T cell-mediated anti-tumor activity, may be a major costimulatory molecule for CD8+ NKT cells. Naïve T cells do not use 4-1BB for costimulation in conjunction with anti-CD3 because 4-1BB is not expressed in naïve T cells. In contrast, CD8+ NKT cells responded to anti-4-lBB vigorously, but did not respond well to anti-CD28 for proliferative response to anti-CD3. 4-1BB was induced selectively in CD8+ NKT cells when stimulated with suboptimal levels of anti-CD3. Conversely, the CD8+ NKT cells showed significantly reduced levels of CD28 compared to other T cells. The CD8+ NKT cells seen in PB were rarely detected : in umbilical cord blood (CB). Therefore, we investigated conditions for production of i comparable subpopulations in CB. Pretreatment of CB T cells with proinflammatory cytokines, IL-15 and IL-12 for 3 to 5 days induced levels of CD8+ NKT cells that are seen in PB as verified by co-expression of NK cell receptors and 4-1BB. CB CD8+ T cells produce IFN-gamma poorly compared to their counterpart cells from PB when costimulated either with anti-CD28 or anti-4-lBB. However, CB CD8+ T cells pretreated with IL-15 and IL-12 produced high levels of IFN-gamma when costimulated with 4-1BB but not with CD28. Our results therefore suggest that 4-1BB may be a primary costimulatory molecule for CD8+ NKT cells. Since CD8+ NKT cells were the most rapidly responding subpopulation to anti-CD3 stimulation among CD8+ T cells, lack of the 4-lBB-dependent NKT cell subpopulations in CB may account for the weak allogenic responses by CB CD8+ T cells previously noted by us (Risdon et al, Cell Immunol, 1994) and the decreased immune reactivity by transplanted CB cells.
|Original language||English (US)|
|Issue number||11 PART I|
|State||Published - Dec 1 2000|
ASJC Scopus subject areas
- Cell Biology