Cutting Edge: IL-7-Independent Regulation of IL-7 Receptor α Expression and Memory CD8 T Cell Development

Klonowski, Kimberly D.; Williams, Kristina; Marzo, Amanda L.; Lefrançois, Leo

doi:10.4049/jimmunol.177.7.4247

Cited by 68 publications

(61 citation statements)

References 31 publications

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“…This point is made most clearly by our data, because the effector cells destined for death (that express KLRG1) could actually be distinguished, and these cells were not saved by the IL-7R␣tg. Our work here also supports and greatly extends two recent studies that suggested IL-7 signals alone do not instruct activated CD8 T cells to express IL-7R␣ or to become memory CD8 T cells (13,26).…”

Section: Discussionsupporting

confidence: 77%

“…Signals emanating from the cytokine receptor for IL-7 are particularly critical for the generation and long-term maintenance of memory CD8 T cells (7-10). Naïve CD8 T cells express IL-7 receptor ␣-chain (IL-7R␣), but during acute viral and bacterial infection, as activated CD8 T cells expand, most down-regulate IL-7R␣ (referred to as IL-7R␣ lo ) (7,8,(11)(12)(13)(14). The small subset of effector cells that expresses IL-7R␣ (referred to as IL-7R␣ hi ) preferentially survives and matures into memory CD8 T cells that express increased amounts of CD27, Bcl-2, and IL-2 and undergo IL-15-driven homeostatic turnover (7,(10)(11)(12)15).…”

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confidence: 99%

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Expression of IL-7 receptor α is necessary but not sufficient for the formation of memory CD8 T cells during viral infection

Hand

Morre²,

Kaech³

2007

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

175

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During many acute viral and bacterial infections, IL-7 receptor ␣-chain (IL-7R␣) is expressed on a subset of effector CD8 T cells that preferentially develop into long-lived memory CD8 T cells. These cells functionally require IL-7R␣, but it is unclear whether IL-7R␣ acts mainly to induce their differentiation into memory cells or to sustain their long-term survival. To examine this question, IL-7R␣ was constitutively overexpressed on all antigen-specific effector CD8 T cells during viral infection. Constitutive IL-7R␣ expression had minimal effects on the numbers or function of effector and memory CD8 T cells formed. This indicated that IL-7R␣ expression is not sufficient to drive memory cell development. In particular, the forced IL-7R␣ expression did not rescue the killer cell lectin-like receptor G1 (KLRG1) hi short-lived effector CD8 T cells from death, showing that the majority of effector CD8 T cells die in an IL-7R␣-independent manner. Moreover, we found that, regardless of the ectopic expression of IL-7R␣, the KLRG1 hi , but not the KLRG1 lo effector CD8 T cells, were unable to proliferate well to IL-7, which may be due to increased amounts of p27 kip in KLRG1 hi cells. Because IL-7 can destabilize p27 kip , this result suggested that KLRG1 hi and KLRG1 lo effector CD8 T cells naturally differ in their ability to transmit IL-7 signals. Altogether, these results reveal that IL-7R␣ expression is permissive, but not instructive, to the creation of memory CD8 T cells.p27kip ͉ T cell homeostasis ͉ T cell memory M emory CD8 T cells form after primary infection and provide long-term protection against subsequent infection due to increased ability to persist and rapidly respond to secondary infections (1, 2). During an infection, antigen-specific CD8 T cells undergo profound clonal expansion and differentiate into effector CD8 T cells that can directly kill infected cells and secrete antiviral cytokines to rapidly control infection (3, 4). After pathogen clearance, the majority of antigen-specific CD8 T cells produced die, and a small number (typically 5-10%) develop into long-lived memory CD8 T cells (4-6). We are interested in elucidating the factors that determine which CD8 T cells will become long-lived memory CD8 T cells. Signals emanating from the cytokine receptor for IL-7 are particularly critical for the generation and long-term maintenance of memory CD8 T cells (7-10). Naïve CD8 T cells express IL-7 receptor ␣-chain (IL-7R␣), but during acute viral and bacterial infection, as activated CD8 T cells expand, most down-regulate IL-7R␣ (referred to as IL-7R␣ lo ) (7,8,(11)(12)(13)(14). The small subset of effector cells that expresses IL-7R␣ (referred to as IL-7R␣ hi ) preferentially survives and matures into memory CD8 T cells that express increased amounts of CD27, Bcl-2, and IL-2 and undergo IL-15-driven homeostatic turnover (7,(10)(11)(12)15). In contrast, most IL-7R␣ lo effector CD8 T cells disappear over this time, but the small numbers that exist at later times typically display reduced expression o...

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Section: Discussionsupporting

confidence: 77%

mentioning

confidence: 99%

Expression of IL-7 receptor α is necessary but not sufficient for the formation of memory CD8 T cells during viral infection

Hand

Morre²,

Kaech³

2007

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

175

View full text Add to dashboard Cite

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“…In both the high and low precursor frequency transfers, IL-7R expression was down-regulated by most cells by day 3 after infection ( compared with day 3. By day 10, all remaining cells expressed levels of IL-7R that were increased over that of naïve TEa cells, as has been previously shown for cells transiting to memory CD8 T cell development (14,32,33). Therefore, regulation of IL-7R expression was not linked to initial precursor frequency and did not correlate with memory cell development.…”

Section: Resultsmentioning

confidence: 49%

Increased competition for antigen during priming negatively impacts the generation of memory CD4 T cells

Blair

Lefrançois

2007

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

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The factors involved in the differentiation of memory CD4 T cells from naïve precursors are poorly understood. We developed a system to examine the effect of increased competition for antigen by CD4 T cells on the generation of memory in response to infection with a recombinant vesicular stomatitis virus. Competition was initially regulated by increasing the precursor frequency of adoptively transferred naïve T cell antigen receptor transgenic CD4 T cells. Despite robust proliferation at high precursor frequencies, memory CD4 T cells did not develop, whereas decreasing the input number of naïve CD4 T cells promoted memory development after infection. The lack of memory development was linked to reduced blastogenesis and poor effector cell induction, but not to initial recruitment or proliferation of antigen-specific CD4 T cells. To prove that availability of antigen alone could regulate memory CD4 T cell development, we used treatment with an mAb specific for the epitope recognized by the transferred CD4 T cells. At high doses, this mAb effectively inhibited the antigen-specific CD4 T cell response. However, at a very low dose of mAb, primary CD4 T cell expansion was unaffected, although memory development was dramatically reduced. Moreover, the induction of effector function was concomitantly inhibited. Thus, competition for antigen during CD4 T cell priming is a major contributing factor to the development of the memory CD4 T cell pool.infection ͉ effector ͉ differentiation ͉ precursor frequency

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“…These differences may have a considerable importance at biological level. Interestingly, a recent paper by Lefrancois and colleagues has demonstrated that both IL-7R␣ regulation and CD8 T cell memory formation occurs in IL-7-independent manner (35). We do not exclude the possibility that sustained IL-7R␣ expression in activated T cells confers a competitive advantage to other homeostatic factors, such as thymic stromal lymphopoietin (TSLP).…”

Section: Discussionmentioning

confidence: 99%

Differential Regulation of Human IL-7 Receptor α Expression by IL-7 and TCR Signaling

Alves

Leeuwen

Derks

et al. 2008

The Journal of Immunology

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IL-7Rα is essential for the development and homeostatic maintenance of mature T cells. Studies in humans and mice have shown that IL-7Rα expression is reduced by its cognate cytokine, IL-7, and Ag, suggesting that active regulation of IL-7 responsiveness is necessary to balance T cell numbers. We show that IL-7- or TCR/CD28-mediated signaling induced a rapid down-regulation of IL-7Rα expression on naive T cells on the mRNA and protein level, with a mild (10-fold) or strong (50-fold) gene suppression, respectively. In both situations, the down-regulation of IL-7Rα was blocked by cyclohexamide and actinomycin D, indicating the involvement of an active mechanism dependent on new transcription and protein synthesis. Upon IL-7 withdrawal, IL-7Rα mRNA and surface protein reappeared in a transcription-dependent manner within 7 h. Yet, IL-7Rα was hardly re-expressed during the same period after TCR/CD28-activation. Likewise, T cells that were activated through CMV in vivo did not re-express IL-7Rα after in vitro culture. Functionally, IL-7-induced down-regulation of IL-7Rα did not hinder the responsiveness of naive T cells to IL-7. Conversely, down-regulation of IL-7Rα on TCR/CD28-activated cells limited IL-7 responsiveness. Strikingly, ectopic expression of IL-7Rα cells on TCR/CD28-activated cells conferred a selective advantage in the response to IL-7. In conclusion, our data show that IL-7- and TCR/CD28-mediated signaling differentially regulate IL-7Rα expression on human T cells with a transient and chronic effect, respectively. The stringent and active regulation of IL-7Rα may constitute a homeostatic mechanism to curtail unwarranted T cell expansion.

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Cutting Edge: IL-7-Independent Regulation of IL-7 Receptor α Expression and Memory CD8 T Cell Development

Cited by 68 publications

References 31 publications

Expression of IL-7 receptor α is necessary but not sufficient for the formation of memory CD8 T cells during viral infection

Expression of IL-7 receptor α is necessary but not sufficient for the formation of memory CD8 T cells during viral infection

Increased competition for antigen during priming negatively impacts the generation of memory CD4 T cells

Differential Regulation of Human IL-7 Receptor α Expression by IL-7 and TCR Signaling

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