αβTCR+ Cells Are a Minimal Fraction of Peripheral CD8+ Pool in MHC Class I-Deficient Mice

Nešić, D.; Santori, Fabio R.; Vukmanović, Stanislav

doi:10.4049/jimmunol.165.4.1896

Cited by 11 publications

(7 citation statements)

References 38 publications

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“…Different rules applied to memory H-Y TCR transgenic T cells, which required expression of class I MHC to survive and proliferate but did not distinguish the presence of cognate or noncognate class I (5). Similar conclusions have been drawn by other groups concerning a homeostatic interaction of CD4 and CD8 T cells with self class II and class I MHC molecules, respectively (6)(7)(8)(9)(10)(11)(12)(13)(14). Those studies concluded that naïve T cells require TCR interactions with self to survive.…”

supporting

confidence: 85%

Homeostatic expansion and phenotypic conversion of naïve T cells in response to self peptide/MHC ligands

Kieper

Jameson

1999

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

311

271

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Recent data suggest that survival of resting, naïve T cells requires an interaction with self MHC molecules. From analysis of the class I MHC-restricted T cell receptor transgenic strain OT-I, we report a different response. Rather than merely surviving, these T cells proliferated slowly after transfer into T-depleted syngeneic hosts. This expansion required both T cell ''space'' and expression of normal levels of self class I MHC molecules. Furthermore, we demonstrate that during homeostatic expansion in a suitable environment, naïve phenotype (CD44 low ) OT-I T cells converted to memory phenotype (CD44 med/high ), despite the absence of foreign antigenic stimulation. On the other hand, cells undergoing homeostatic expansion did not acquire cytolytic effector function. The significance of these data for reactivity of T cells with self peptide͞ MHC ligands and the implications for normal and abnormal T cell homeostasis are discussed. During thymic development, T cells require an interaction of their clone-specific T cell receptor (TCR) with self peptide͞ MHC ligands to survive the process of positive selection (1). Once T cell maturation is complete, however, it has been assumed that such reactivity toward self is lost (inherent in the idea of self tolerance) and that the TCR played no significant role in the survival of resting naïve T cells, before encounter with foreign antigen. This image of the TCR playing the role of ''Sleeping Beauty,'' waiting for the appropriate peptide͞MHC ligand to activate the T cell from its rest, has been challenged by recent data suggesting a ''Red Queen'' analogy is closer to the mark, i.e., that naïve T cells require a constant engagement of the TCR with self ligands simply to persist in an quiescent state (2, 3). Thus, together with a pivotal role for certain cytokines (4), TCR interactions with self may be critical for maintenance of the naïve T cell population.The most extensive analysis of this phenomena involved adoptive transfer of T cells bearing the anti-H-Y͞D b TCR transgene (H-Y TCR) into irradiated hosts (5). These studies showed that naïve CD8 T cells survived for long periods of time in the presence of cognate self MHC molecules (i.e., in that case, H-2D b ) and persisted as resting cells in the absence of stimulatory antigen. These same cells disappeared from the secondary lymphoid tissue in the absence of this class I MHC molecule, even if another class I molecule (K b ) was present, suggesting a correlation between survival and TCR recognition of self. Different rules applied to memory H-Y TCR transgenic T cells, which required expression of class I MHC to survive and proliferate but did not distinguish the presence of cognate or noncognate class I (5). Similar conclusions have been drawn by other groups concerning a homeostatic interaction of CD4 and CD8 T cells with self class II and class I MHC molecules, respectively (6-14). Those studies concluded that naïve T cells require TCR interactions with self to survive.We sought to extend these findings by usin...

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supporting

confidence: 85%

Homeostatic expansion and phenotypic conversion of naïve T cells in response to self peptide/MHC ligands

Kieper

Jameson

1999

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

311

271

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“…This supports the existence of peripheral homeostasis (2,3,12,(30)(31)(32), because neither the rate nor the composition of thymic-exported cells varies in response to changes in the peripheral T cell pool (11,20). Theoretically, T cell numbers could be restricted by the finite availability of signals similar to those required for naïve CD4 (33)(34)(35), CD8 (18,36), and memory (see refs. 37 and 38 for reviews) T cell survival.…”

Section: Fig 5 (A)supporting

confidence: 55%

A central role for thymic emigrants in peripheral T cell homeostasis

Berzins

Godfrey

Miller

et al. 1999

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

145

123

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After initial seeding by thymic emigrants, homeostatic regulation of the T cell pool has been thought to occur entirely within the periphery. Here we report that the degree of thymic emigration directly affects the number and the CD4͞CD8 ratio of peripheral T cells. We demonstrate that the increase in T cell pool size caused by the engraftment of 2, 6, or 9 thymic lobes correlates almost exactly with the number of emigrants exported from those grafts in the previous 3 weeks, regardless of how long the graft has been in place. The extent of the increase supports the concept of a 3-week period after thymic export in which emigrant T cells are exempt from peripheral T cell homeostasis. This apparent exclusion of recent thymic emigrants from the niche-based regulation of peripheral T cell numbers ensures repertoire turnover throughout adult life and provides the basis of a direct and previously unrecognized role for the thymus in the regulation of peripheral T cell homeostasis.There is a consensus emerging that T cell numbers are regulated through competition for a finite number of essential survival factors (1-3). These factors, collectively termed niches, are thought to provide stability in the T cell pool through the removal of excess cells when all niches are occupied and the proliferation and͞or increased longevity of peripheral T cells when niches are vacant. Although consistent with the stable pool size of normal young animals, this hypothesis is inconsistent with long-term changes to T cell numbers caused by age (4, 5), disease (6-8), and experimental manipulations (9-11). Many of these instances are also associated with changes to the rate of thymic export and support our earlier study (11) demonstrating a persistent role for the thymus in peripheral T cell regulation.Studies involving the reconstitution of lymphocyte-depleted mice have shown that the number and CD4͞CD8 ratio of T cells can be restored through the peripheral expansion of adoptively transferred cells, irrespective of the number or type of T cells injected (3,(12)(13)(14)(15). These reports imply that the thymus has only a minor influence on the adult T cell pool, simply acting as a source of new T cells to be subsequently regulated within the periphery (16). However, it is not clear whether reconstitution of a lymphocyte-deficient environment is comparable to maintaining the diverse repertoire of normal mice. Recent studies have demonstrated that expansion triggered by lymphopenia is restricted to the activated͞memory pool, whereas generation of the naive T cell pool depends on thymic export (13,17,18). This provided an explanation for the gross overrepresentation of memory T cells in the T cell pool after reconstitution (14,19) and raised the important question of whether the thymus responds to feedback from the peripheral T cell pool to regulate naïve T cell numbers (14). We tested this and found that the number and CD4͞CD8 ratio of recent thymic emigrants was independent of the number and CD4͞ CD8 ratio of peripheral T cells (20)....

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“…It has been recently reported that most of the CD8 ϩ cells in ␤ 2 -M Ϫ/Ϫ animals do not express CD8␤, but express high levels of CD11c and CD11b, suggesting that they may be of dendritic cell lineage (19). In addition, CD8␣␣ T cells have been shown to be CD44 high (20).…”

Section: Phenotype Of Cd8 ϩ T Cells From Mhc Class Ia-deficient Micementioning

confidence: 99%

Memory Phenotype of CD8+ T Cells in MHC Class Ia-Deficient Mice

Kurepa

Forman

2003

The Journal of Immunology

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B6.Kb−Db− mice are devoid of class Ia but express normal levels of class Ib molecules. They have low levels of CD8 T cells in both the thymus as well as peripheral T cell compartments. Although the percentage of splenic CD8αα T cells is increased in these animals, ∼90% of CD8 T cells are CD8αβ. In contrast to B6 animals, most of the CD8 T cells from these mice have a memory phenotype (CD44highCD122high CD62Llow) including both CD8αβ and CD8αα subsets. In the thymus of B6.Kb−Db− animals, there is a decrease in the percentage of SP CD8 T cells, although most are CD44low, similar to that seen in B6 mice. The spleens from day 1-old B6 and B6.Kb−Db− mice have a relatively high proportion of CD44highCD62Llow CD8 T cells. However, by day 28 most CD8 T cells in B6 mice have a naive phenotype while in B6.Kb−Db− mice the memory phenotype remains. Unlike CD44high cells that are found in B6 animals, most CD44high cells from B6.Kb−Db− mice do not secrete IFN-γ rapidly upon activation. The paucity of CD8 T cells in B6.Kb−Db− mice might be due in part to their inability to undergo homeostatic expansion. Consistent with this, we found that CD8 T cells from these animals expand poorly in X-irradiated syngeneic hosts compared with B6 CD8 T cells that respond to class Ia Ags. We examined homeostatic expansion of B6 CD8 T cells in single as well as double class Ia knockout mice and were able to estimate the fraction of cells reactive against class Ia vs class Ib molecules.

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αβTCR+ Cells Are a Minimal Fraction of Peripheral CD8+ Pool in MHC Class I-Deficient Mice

Cited by 11 publications

References 38 publications

Homeostatic expansion and phenotypic conversion of naïve T cells in response to self peptide/MHC ligands

Homeostatic expansion and phenotypic conversion of naïve T cells in response to self peptide/MHC ligands

A central role for thymic emigrants in peripheral T cell homeostasis

Memory Phenotype of CD8+ T Cells in MHC Class Ia-Deficient Mice

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