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. 2012 Apr 9;209(4):641-51.
doi: 10.1084/jem.20112071. Epub 2012 Mar 26.

Naive T cells are dispensable for memory CD4+ T cell homeostasis in progressive simian immunodeficiency virus infection

Afam A Okoye  1 , Mukta Rohankhedkar, Chike Abana, Audrie Pattenn, Matthew Reyes, Christopher Pexton, Richard Lum, Andrew Sylwester, Shannon L Planer, Alfred Legasse, Byung S Park, Michael Piatak Jr, Jeffrey D Lifson, Michael K Axthelm, Louis J Picker
Affiliations

Naive T cells are dispensable for memory CD4+ T cell homeostasis in progressive simian immunodeficiency virus infection

Afam A Okoye et al. J Exp Med. .

Abstract

The development of AIDS in chronic HIV/simian immunodeficiency virus (SIV) infection has been closely linked to progressive failure of CD4(+) memory T cell (T(M)) homeostasis. CD4(+) naive T cells (T(N)) also decline in these infections, but their contribution to disease progression is less clear. We assessed the role of CD4(+) T(N) in SIV pathogenesis using rhesus macaques (RMs) selectively and permanently depleted of CD4(+) T(N) before SIV infection. CD4(+) T(N)-depleted and CD4(+) T(N)-repleted RMs were created by subjecting juvenile RMs to thymectomy versus sham surgery, respectively, followed by total CD4(+) T cell depletion and recovery from this depletion. Although thymectomized and sham-treated RMs manifested comparable CD4(+) T(M) recovery, only sham-treated RMs reconstituted CD4(+) T(N). CD4(+) T(N)-depleted RMs responded to SIVmac239 infection with markedly attenuated SIV-specific CD4(+) T cell responses, delayed SIVenv-specific Ab responses, and reduced SIV-specific CD8(+) T cell responses. However, CD4(+) T(N)-depleted and -repleted groups showed similar levels of SIV replication. Moreover, CD4(+) T(N) deficiency had no significant effect on CD4(+) T(M) homeostasis (either on or off anti-retroviral therapy) or disease progression. These data demonstrate that the CD4(+) T(N) compartment is dispensable for CD4(+) T(M) homeostasis in progressive SIV infection, and they confirm that CD4(+) T(M) comprise a homeostatically independent compartment that is intrinsically capable of self-renewal.

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Figures

Figure 1.
Figure 1.
Thymectomy abrogates CD4+ TN recovery after antibody-mediated CD4+ T cell depletion. (A) Schematic representation of the experimental protocol used in this study. (B–J) Analysis of CD4+ and CD8+ TN (dashed lines) and TM (solid lines) population dynamics after mAb huOKT4A treatment in RMs with complete initial CD4+ T cell depletion in blood that were previously subjected to thymectomy (red, n = 9) versus sham surgery (blue, n = 9). Results (mean + SEM) are shown as percentage of baseline, or for percentage of Ki-67+, change (Δ) from baseline (see Materials and methods). Note that T cells in BAL and small intestinal mucosa are essentially all TM (Pitcher et al., 2002). The significance of differences in these parameters between the thymectomized and sham-treated groups at day 238 (day 105 for small intestinal mucosa cells) after first mAb dose was assessed as described in the Materials and methods (significant p-values shown; NS, nonsignificant). (K) Comparison of the frequency of RhCMV-responsive cells within the CD4+ memory populations of blood and BAL at day 238 after depletion. Shown are box plots, with boxes and whiskers indicating interquartile ranges (25th–75th percentiles) and 10th–90th percentile values, respectively. (L) Analysis of CD4+ TN (blue) and CD4+ TM (red) dynamics (absolute counts and proliferative fraction; mean + SEM) in three thymectomized RMs with incomplete initial CD4+ T cell depletion in blood (mean of 95% at day 21) after mAb huOKT4A treatment. (M) Flow cytometric profiles of blood and peripheral LN TN versus TM subsets from representative thymectomized and sham-treated RMs before and after complete CD4+ T cell depletion. The CD28 versus CD95 profiles shown were gated on CD3+/CD4+ small lymphocytes with red lines delineating the position of the TN cluster. Multiparameter analysis (see Materials and methods) was used for the actual quantification of TN versus TM, with the percentage of TN shown in red.
Figure 2.
Figure 2.
CD4+ TN-deficient RMs display SIV replication dynamics similar to control RMs despite attenuated SIV-specific T cell and Ab responses. (A) Comparison of pvl, CD4+ TM depletion, CD4+ TM proliferative responses, and the magnitude of SIV-specific CD8+ T cell responses at day 70 pi between the CD4+ TN -repleted control group (n = 9) and unmanipulated RMs (n = 6) challenged with the same SIVmac239 virus. Shown are box plots, with boxes and whiskers indicating interquartile ranges (25th–75th percentiles) and 10th–90th percentile values, respectively. Significance of differences in these parameters between groups was assessed as described in the Materials and methods (NS, nonsignificant). (B–G) Comparison of the indicated parameters (mean + SEM) over the course of SIVmac239 infection between the CD4+ TN-depleted and CD4+ TN-repleted groups (n = 9 each). The period over which all RMs received ART (day 70–156 pi) is shown in gray. The inset in E shows the percentage of RMs in the CD4+ TN-depleted (red) and TN-repleted (blue) RM groups that displayed a measureable anti-SIVenv neutralizing Ab response (e.g., seroconverted) before ART. Differences in these parameters between the CD4+ TN-depleted and CD4+ TN-repleted groups were statistically analyzed as described in the Materials and methods, with brackets indicating time points that were grouped together for analysis (significant p-values shown).
Figure 3.
Figure 3.
CD4+ TN deficiency does not compromise CD4+ TM homeostasis in progressive and partially suppressed SIV infection. (A–D) Comparison of the dynamics (absolute counts and proliferative fraction; mean + SEM) of overall CD4+ TM and the TCM, TTrEM, and TEM subsets in blood, the percentage of CD4+ of total CD3+ (memory) T cells in BAL, and absolute counts of CD4+ TM with a regulatory phenotype (CD25+/FoxP3+) in blood of CD4+ TN-depleted (red, n = 9) versus -repleted RMs (blue, n = 9) over the course of SIV infection (as in Fig. 1 A). The significance of differences in these parameters between RM groups in the indicated regions was assessed as described in the Materials and methods (significant p-values shown; NS, nonsignificant). (E) Comparison of the change in the percentage of Ki-67+ CD4+ TM in peripheral LN of CD4+ TN-depleted versus –repleted RMs between days 70 (ART day 0) and 73 (3 d after ART). Note that the increase in the percentage of Ki-67+ cells from day 70 to 73 was significant in both groups (p-values shown), but the magnitude of this increase (Δ%Ki-67) was not different between groups. (F and G) Comparison of the dynamics of CD8+ TM in the blood of CD4+ TN-depleted versus –repleted RMs over the course of SIV infection (mean + SEM), with statistical analysis of the indicated regions.
Figure 4.
Figure 4.
CD4+ TN deficiency does not accelerate disease progression. (A) Kaplan-Meier plot of the time to end-stage AIDS (day of disease mandated necropsy) for CD4+ TN-depleted (red, n = 9) versus -repleted RMs (blue, n = 9) over the 1 yr of follow-up. Log rank analysis indicated that rate of progression to AIDS between the two groups was not significantly different (P = 0.72). (B) Major pathological findings at necropsy of study RMs progressing to end-stage AIDS (n = 5 and 4 for CD4+ TN-depleted vs. -repleted RMs, respectively). (C) Flow cytometric profiles (as described in Fig. 1 M) of CD4+ T cell populations in blood and various LNs at necropsy of representative CD4+ TN-depleted (#24273, progression to AIDS at day 190 pi) and CD4+ TN-repleted (#25522, progression to AIDS at day 163 pi) RMs. The percentage of TN of gated events (total CD4+ T) is shown in red in the bottom left. The percentage of CD4+ of total T cells is shown in black at the top right. (D) Comparison of CD4+/CD8+ ratios within the TM populations in blood and selected secondary lymphoid tissues (axillary and inguinal LNs and spleen) and effector sites (liver, BAL, and small intestinal mucosa) of four of five CD4+ TN-depleted (red) and four of four CD4+ TN-repleted (blue) RMs studied at necropsy (one CD4+ TN-depleted RM could not be analyzed as a result of inadequate staining of cell preparations obtained at necropsy). Shown are box plots, with boxes and whiskers indicating interquartile ranges (25th–75th percentiles) and 10th–90th percentile values, respectively. Statistical analysis of differences in this parameter between groups was analyzed as described in the Materials and methods (NS, nonsignificant).
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