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. 2015 Nov 1;195(9):4292-305.
doi: 10.4049/jimmunol.1500609. Epub 2015 Sep 28.

Effect of IL-7 Therapy on Naive and Memory T Cell Homeostasis in Aged Rhesus Macaques

Afam A Okoye  1 , Mukta Rohankhedkar  1 , Audrie L Konfe  1 , Chike O Abana  1 , Matthew D Reyes  1 , Joseph A Clock  1 , Derick M Duell  1 , Andrew W Sylwester  1 , Partha Sammader  2 , Alfred W Legasse  1 , Byung S Park  3 , Michael K Axthelm  1 , Janko Nikolich-Žugich  4 , Louis J Picker  5
Affiliations

Effect of IL-7 Therapy on Naive and Memory T Cell Homeostasis in Aged Rhesus Macaques

Afam A Okoye et al. J Immunol. .

Abstract

Aging is associated with gradual deterioration of adaptive immune function, a hallmark of which is the profound loss of naive T cells (TN) associated with decline in thymic output and export of new cells into the peripheral T cell pool. Because the lymphotropic cytokine IL-7 plays crucial roles in both development of TN in the thymus and TN homeostasis in the periphery, we sought to determine the extent to which therapeutic administration of IL-7 could reverse TN deficiency in aging rhesus macaques (RM), either by enhancement of the demonstrably reduced thymopoiesis or by peripheral TN expansion. Our results indicate that treatment of both adult (8-15 y) and old (>20 y) RM with recombinant simian IL-7 (rsIL-7) results in only transient increases in peripheral CD4(+) and CD8(+) TN numbers with no long-term benefit, even with repeated therapy. This transient effect was due to peripheral TN expansion and not enhanced thymic function, and appeared to be limited by induction of IL-7 nonresponsiveness. However, rsIL-7 therapy had a more promising effect on the central memory T cell (TCM) population (both CD4(+) and CD8(+)) in adult and old RM, doubling the numbers of these cells in circulation and maintaining this larger population long term. IL-7 therapy did not reduce TCR diversity of the memory T cell compartment, suggesting that rsIL-7-induced expansion was symmetrical. Thus, although rsIL-7 failed to counter age-associated TN loss, the ability of this therapy to expand clonotypically diverse CD4(+) and CD8(+) TCM populations might potentially improve adaptive immune responsiveness in the elderly.

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Conflict of interest statement

Disclosures: All authors have no financial conflicts of interest.

Figures

Figure 1
Figure 1. Thymectomy abrogates CD8+ TN recovery after antibody-mediated CD8+ T cell depletion
Analysis of CD8+ TN and TM population dynamics, including TCM, TTrM and TEM subsets after mAb cM-T807 treatment in RM with complete initial CD8+ T cell depletion in blood that were previously subjected to thymectomy (n=8) or sham surgery (n=8). Results (mean + SEM) are shown as change from baseline value, with baseline represented as 100% and subsequent changes are shown relative to this baseline value determined as the average of absolute counts (see materials and methods) at days -14, -7 and 0 relative to the first dose of cM-T807.
Figure 2
Figure 2. Thymic function persists in old RM
(a) Comparison of the CD8+ TN absolute counts in peripheral blood of old (>20 years, n=20), adult (8–15 years, n=20) and young (0–6 years, n=20) RM. The p value was obtained using Kruskal-Wallis test to compare difference between groups (significant p values are shown; NS, non-significant). (b) Representative flow cytometric profiles showing decline in the fractional representation of CD8+ TN in blood of RM with age. The CD28 vs. CD95 profiles shown were gated on CD3+, CD8+, small lymphocytes. The red lines delineate the border between CD95low TN and CD95high TM with % of gated events in the naïve cluster shown in black. (c) Comparison of the recovery of CD8+ TN absolute counts (shown as percentage of baseline) in blood of old (n=4) vs. adult (n=4) vs. young (n=10) RM after cM-T807 treatment. Significance of difference in the rates of CD8+ TN recovery between age groups was assessed as described in the materials and methods.
Figure 3
Figure 3. The production and T cell responsiveness to IL-7 are maintained in old RM
(a) Comparison of plasma IL-7 concentrations in old (n=25) vs. adult (n=22) vs. young (n=25) RM. The p value was obtained using Kruskal-Wallis test to compare difference in concentration between groups (NS = non-significant). (b) Comparison of the dose response curves of pSTAT5 expression in peripheral blood CD4+ and CD8+ T cells between old (n=7) vs. adult (n=4) RM after ex vivo stimulation with 0, 0.5, 1, 2, 4, 8, 16, 32, 64, 128 ng/mL of rsIL-7 or IL-15. Results (mean + SEM) are shown as change from baseline (Δ) and significance of difference was assessed as described in the materials and methods (NS, non-significant).
Figure 4
Figure 4. Clustered rsIL-7 dosing does not enhance TN reconstitution
(a) A schematic representation of the clustered rsIL-7 dosing regimen in which 3 weekly s.c. injections (30µg/kg) followed by 2 weeks of no therapy and then 2 repeat cycles of therapy were administered (on days 0, 7, 14, 35, 42, 49, 70, 77 and 84) to 5 adult (10–12 years) and 6 old (>20 years) RM. (b) Analysis of the proliferative fraction and absolute counts of CD4+ TN and CD8+ TN, and (c) CD4+ TM and CD8+ TM in blood after clustered rsIL-7 treatment. Results (mean + SEM) are shown as percentage of Ki-67+, change (Δ) from baseline or absolute counts percentage of baseline. Significance of differences in these parameters between age groups was assessed as described in the materials and methods (*p < 0.05 at each time point).
Figure 5
Figure 5. Long-term repeated single dosing with rsIL-7 has transient effects on CD4+ and CD8+ TN counts
(a) A schematic representation of the dosing protocol in which 4 adult (8–13 years) and 7 old (>20 years) RM received 7 s.c. injections (30µg/kg) of rsIL-7 on days 0, 7, 108, 304, 423 and 542. (b) Analysis of the absolute counts and proliferative fraction of CD4+ and CD8+ TN in the blood after each dose of rsIL-7. Results (mean + SEM) are shown as percentage of Ki-67+, change (Δ) from baseline or absolute counts percentage of baseline. Significance of differences between age groups was assessed as described in the materials and methods (significant p values are shown; NS, non-significant).
Figure 6
Figure 6. Long-term rsIL-7 dosing has a sustained effect on CD4+ TCM counts
Figure shows the comparison of the absolute counts and proliferative fraction of CD4+ TM subsets in the blood. Results (mean + SEM) are shown as percentage of Ki-67+, change (Δ) from baseline or absolute counts percentage of baseline. Significance of differences in these parameters between age groups was assessed as described in the materials and methods (significant p values are shown; NS, non-significant).
Figure 7
Figure 7. The effect of rsIL-7 dosing on CD8+ TCM counts was similar between adult and old RM
Figure shows the comparison of the absolute counts and proliferative fraction of CD8+ TM subsets in the blood. Results (mean + SEM) are shown as percentage of Ki-67+, change (Δ) from baseline or absolute counts percentage of baseline. Significance of differences in these parameters between age groups was assessed as described in the materials and methods (significant p values are shown; NS, non-significant).
Figure 8
Figure 8. The comparison of the effect of rsIL-7 therapy on TCRBV repertoire diversity between adult and old RM
CDR3 length polymorphism analysis (spectratyping) was conducted for FACS-sorted total naïve (CD95low) and memory (CD95hi) CD4+ and CD8+ T cells for 24 BV families. Diversity complex index (DCI) statistical analysis profile was created from sorted CD4+ naïve and memory (a, b) and CD8+ naïve and memory (c, d) T cells, respectively. Positive DCI value indicates potential improvement of spectratype profile, while negative DCI value indicates potential loss of spectratype profile diversity. DCI value is zero when two distributions are identical.
Figure 9
Figure 9. IL-7-induced T cell expansion is independent of a thymus
(a) Comparison of CD4+ and CD8+ TN and TM dynamics (absolute counts and proliferative fraction) in the blood of juvenile thymectomized (n=6) vs. sham (n=6)-treated RM after s.c. injections (30µg/kg) of rsIL-7 on days 0 and 7. Results (mean + SEM) are shown as percentage of Ki-67+, change (Δ) from baseline or absolute counts percentage of baseline. Significance of differences in these parameters between groups was assessed as described in the materials and methods (NS, non-significant) (b) Both groups of thymectomized and sham-treated RM were administered four daily i.v. doses (30 mg/kg) of BrdU beginning day 10 after the first rsIL-7 injection, and samples were obtained before BrdU administration (day 0) and at subsequent intervals for flow cytometric analysis of BrdU incorporation in CD4+ and CD8+ TN and TM. The first post-BrdU sampling was 24 h after the last BrdU dose and is designated day 1. The percentage of total BrdU+ cells was determined at each time point. Results (mean + SEM) are shown as percentage of BrdU+ change (Δ) from baseline. The significance of differences in BrdU decay kinetics between thymectomized and sham-treated RM was statistically analyzed as described in the materials and methods (NS, non-significant).
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