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. 2010 Jan 1;184(1):35-44.
doi: 10.4049/jimmunol.0803355. Epub 2009 Nov 30.

IL-15 regulates both quantitative and qualitative features of the memory CD8 T cell pool (VSports注册入口)

Michelle M Sandau  1 , Jacob E Kohlmeier, David L Woodland, Stephen C Jameson
Affiliations

IL-15 regulates both quantitative and qualitative features of the memory CD8 T cell pool (VSports注册入口)

Michelle M Sandau et al. J Immunol. .

Abstract

Memory T cells are critical for immunity to various intracellular pathogens. Recent studies have indicated that CD8 secondary memory cells, induced by prime-boost approaches, show enhanced protective function compared with primary memory cells and exhibit phenotypic and functional characteristics that distinguish them from primary memory cells. However, little is known about the cytokine requirements for generation and maintenance of boosted memory CD8 T cells. We studied the role of IL-15 in determining the size and composition of the secondary (2 degrees) memory CD8 T cell pool induced by Listeria monocytogenes infection in mice. Following boosting, IL-15-deficient animals failed to generate a subset of CD8 effector memory cells, including a population of IL-7Ralpha(low) cells, which were prominent among secondary memory cells in normal mice. IL-15 deficiency also resulted in changes within the IL-7Ralpha(high)CD62L(low) subset of 2 degrees memory CD8 T cells, which expressed high levels of CD27 but minimal granzyme B. In addition to these qualitative changes, IL-15 deficiency resulted in reduced cell cycle and impaired Bcl-2 expression by 2 degrees memory CD8 T cells, suggesting a role for IL-15 in supporting both basal proliferation and survival of the pool. Analogous qualitative differences in memory CD8 T cell populations were observed following a primary response to Sendai virus in IL-15(-/-) animals. Collectively, these findings demonstrate that IL-15 plays an important role in dictating the composition rather than simply the maintenance of the CD8 memory pool. VSports手机版.

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Figures

Figure 1
Figure 1. IL-15 influences the maintenance and basal proliferation of 2° memory CD8 T cells
A) B6 and IL-15-/- mice were primed and boosted with LM-ova as indicated. The number of endogenous splenic Ova/Kb specific CD8 T cells were enumerated by multiplying the percentage of Ova/Kb+ CD8+ cells present by the total number of cells recovered. B) 104 OT-I T cells were adoptively transferred into B6 mice which were then primed and boosted with LM-OVA. At day 5 of boosting, bulk CD8 T cells were transferred into B6 and IL-15-/- hosts and recovery of donor OT-I cells in these secondary hosts determined 23 days later. C) B6 and IL-15-/- animals were adoptively transferred with 104 OT-I T cells and primed/boosted as indicated. The mice were placed on BrdU drinking water for 14 days and then the percentage of OT-I cells showing BrdU incorporation was determined. Statistical differences (p<0.003) were observed between the following pair wise combinations: 1° memory B6 vs IL-15-/-; 2° memory B6 vs IL-15-/- and B6 1° vs. 2°; but not (p>0.05) IL-15-/- 1° vs. 2°. A and C are representative data from at least 3 experiments, while B is representative of 2 experiments.
Figure 2
Figure 2. IL-15 deficiency affects the expression of CD27 and CCR7, but not CD62L
2° memory OT-I from the spleens of B6 and IL-15-/- hosts were assessed for the surface expression of indicated markers. A) histogram of CD62L expression of 2° memory cells; cells from the B6 host filled grey histogram; cells from IL-15-/- host are solid black line; bulk CD8 T cells from B6 host dashed black line. B) co-expression of CD62L and either CD27 or CCR7. These data are representative data from at least 4 experiments (A) and 2 experiments (B).
Figure 3
Figure 3. IL-15 maintains CD127 low 2° memory cells
1° and 2° memory OT-I cells from the spleens of B6 and IL-15-/- were assessed for phenotypic changes. A) 1° memory (left panel) or 2° memory (middle panel) were assessed for CD127 expression. In addition, boosted OT-I T cells were used for secondary adoptive transfer into B6 and IL-15-/- hosts (as in Fig 1B) and were assessed for CD127 expression (right panel). Cells recovered from: B6 hosts are filled grey histograms; from IL-15-/- hosts are solid black line; endogenous CD8 T cell expression from B6 mice are dashed black lines. B) Co-expression of CD127 and CD62L from 2° memory OT-I in the indicated hosts. C) Histogram of CD27 expression of 2° memory cells: from IL-15-/- mice gating on CD127high and CD62Llow is the solid black line: from B6 mice gating on CD127high and CD62Llow is the shaded grey histogram; and from B6 mice gating on CD127low and CD62Llow is the dashed black lines. These data are representative data from at least 4 experiments (A and B) and 2 experiments (C).
Figure 4
Figure 4. IL-15 deficiency alters the primary memory CD8 T cell pool following respiratory infection with Sendai virus
B6 and IL-15-/- mice were infected with 250 EID50 Sendai virus and were rested for 65 days. A) Splenocytes were isolated, antigen specific cells identified using anti-CD8 and SenNP324-332Kb tetramer and phenotypic analysis performed for the indicated markers. B) The frequency of Sendai-specific CD8 T cells with the indicated phenotype is shown (mean ± s.d.) for B6 (filled bars) and IL-15-/- (open bars) mice. Significant differences between B6 and IL-15-/- mice are denoted with an asterisk (p<0.05). The data are representative of 3 mice per group from 2 independent experiments.
Figure 5
Figure 5. IL-15 does not regulate cytokines production from either 1° or 2° memory cells
B6 and IL-15-/- mice adoptively transferred with naïve OT-I.PL T cells were primed or primed/boosted with LM-OVA as indicated. At least 30 days following the last infection, bulk splenocytes cells from the indicated mice were stimulated with OVAp in vitro and production of IFNγ (A) TNFα, (B) and IL-2 (C) in the donor OT-I cells assessed by intracellular staining. The data show the percent of OT-I T cells producing each cytokine following antigen stimulation. These are representative data from at least 4 experiments.
Figure 6
Figure 6. Sustained expression of granzyme B depends on IL-15
1° and 2° memory OT-I cells from indicated hosts were recovered from spleens and analysed A) Expression levels of granzyme B on 1° and 2° memory cells from the indicated hosts and is expressed as MFI. B) Co-expression of Granzyme B and either CD62L (top row) or CD127 (bottom row). These are representative data from at least 3 experiments.
Figure 7
Figure 7. Bcl-2 expression is increased in the presence of IL-15
1° and 2° memory OT-I cells from indicated hosts were recovered from spleens and stained for CD127 and either BrdU or Bcl-2. A) BrdU incorporation was carried out as described in Fig 1C. These data are represented by first subsetting on CD127 expression, and then determining the percentage of BrdU incorporation within that population. Asterisks indicate that too few events were recorded for accurate evaluation. B) Expression level of intracellular Bcl-2 (as MFI) in OT-I cells from the indicated hosts. C) Co-expression of Bcl-2 expression and CD127 in OT-I cells from the indicated hosts D) 2° memory OT-I CD8 T cells were subsetted based on CD127 expression and the expression of Bcl-2 (MFI) was determined from cells of the indicated hosts. These are representative data from at least 3 experiments.
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References

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