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

Abstract

(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...

Enrichment and Persistence of Virus-Specific CTL in the Brain of Simian Immunodeficiency Virus-Infected Monkeys Is Associated with a Unique Cytokine Environment

“…Therefore, the elevated levels of IL-15 in the CNS following SIV infection could be involved in maintaining local CTL, including clones that disappear from the rest of the body. The fact that brain-derived cells are more susceptible to IL-15 than cells from spleen may relate to a distinct subset of CD8 ϩ T cells, as found in rodents, which is highly dependent upon IL-15 (31). Their potential enrichment in the brain vs the spleen would help explain the differential effect of IL-15 on brain CD8 T cells.…”

The Protein Tyrosine Kinase Tec Regulates a CD44highCD62L− Th17 Subset

“…Because Th1 or Th2 memory cells were not increased, this indicated a general bias toward a Th17 memory in Tec 2/2 mice. We consider it unlikely that this CD44 high subset represents an innate-like lineage with immediate effector function similar to the increase in innate-like T cells observed in Itk-deficient mice (29)(30)(31)(32)(33) or that a natural Th17 population as described recently (34) + T cells subset with Th17 characteristics is enhanced in the absence of Tec. In vitro, Th17 differentiation from naive CD4 + T cells was shown to occur upon anti-CD3ε/CD28 stimulation in the presence of IL-6 plus TGF-b1 (27); however, other cytokines were shown to contribute to the differentiation and homeostatic maintenance of Th17 cells (19,36,37).…”

Positive selecting cell type determines the phenotype of MHC class Ib-restricted CD8 + T cells

“…It is therefore possible that Eomes plays a role in determining the phenotype of M3-restricted CD8 + T cells. In addition to comparing Eomes expression between D7 TEC s and D7 HC s, we were interested in comparing the expression levels of CD122 (the receptor specifying IL-15 responsiveness), which, similar to CD44, is expressed at a high level on innate T cells under naive conditions (30).…”