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. 2008 Apr 15;180(8):5582-92.
doi: 10.4049/jimmunol.180.8.5582.

CD127 and CD25 expression defines CD4+ T cell subsets that are differentially depleted during HIV infection

Richard M Dunham  1 , Barbara Cervasi, Jason M Brenchley, Helmut Albrecht, Amy Weintrob, Beth Sumpter, Jessica Engram, Shari Gordon, Nichole R Klatt, Ian Frank, Donald L Sodora, Daniel C Douek, Mirko Paiardini, Guido Silvestri
Affiliations

CD127 and CD25 expression defines CD4+ T cell subsets that are differentially depleted during HIV infection

Richard M Dunham et al. J Immunol. .

Abstract

Decreased CD4(+) T cell counts are the best marker of disease progression during HIV infection. However, CD4(+) T cells are heterogeneous in phenotype and function, and it is unknown how preferential depletion of specific CD4(+) T cell subsets influences disease severity. CD4(+) T cells can be classified into three subsets by the expression of receptors for two T cell-tropic cytokines, IL-2 (CD25) and IL-7 (CD127). The CD127(+)CD25(low/-) subset includes IL-2-producing naive and central memory T cells; the CD127(-)CD25(-) subset includes mainly effector T cells expressing perforin and IFN-gamma; and the CD127(low)CD25(high) subset includes FoxP3-expressing regulatory T cells. Herein we investigated how the proportions of these T cell subsets are changed during HIV infection. When compared with healthy controls, HIV-infected patients show a relative increase in CD4(+)CD127(-)CD25(-) T cells that is related to an absolute decline of CD4(+)CD127(+)CD25(low/-) T cells. Interestingly, this expansion of CD4(+)CD127(-) T cells was not observed in naturally SIV-infected sooty mangabeys. The relative expansion of CD4(+)CD127(-)CD25(-) T cells correlated directly with the levels of total CD4(+) T cell depletion and immune activation. CD4(+)CD127(-)CD25(-) T cells were not selectively resistant to HIV infection as levels of cell-associated virus were similar in all non-naive CD4(+) T cell subsets. These data indicate that, during HIV infection, specific changes in the fraction of CD4(+) T cells expressing CD25 and/or CD127 are associated with disease progression. Further studies will determine whether monitoring the three subsets of CD4(+) T cells defined based on the expression of CD25 and CD127 should be used in the clinical management of HIV-infected individuals.

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Conflict of interest statement

Disclosures: The authors have no financial conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Expression of CD127 and CD25 defines three subsets of CD4+ T cells. A, Gating strategy for defining subsets of CD4+ T cells using CD127 and CD25. Plots shown are gated on lymphocytes, then CD3+, CD8−, and CD4+. B, Comparison of the average fraction of CD4+ T cells within each subset in HIV-infected (filled bars) and uninfected (open bars) individuals. ***, p < 0.001 (two-way ANOVA). C, Comparison of the absolute number of CD4+ T cells within each subset in HIV-infected individuals (filled bars) and uninfected (open bars) controls.
FIGURE 2
FIGURE 2
CD127−CD25−CD4+ T cells express phenotypic and functional markers of effector T cells. Average fraction (A) and absolute number (B) of cells, within each of the three subsets of CD4+ T cells identified based on the expression of CD127 and CD25, that can be defined as naive (CD45RA+CD62L+), central memory (CD45RA−CD62L+), or effector memory (CD62L−) CD4+ T cells in HIV-infected (left) and uninfected (right) individuals. **, p < 0.01; ***, p < 0.001 (two-way ANOVA). C, Average proportion of activation marker expression by each CD127/CD25 CD4+ T cell subset in HIV-infected (left) and uninfected (right) individuals. **, p < 0.01; ***, p < 0.001 (one-way ANOVA comparing between CD127/CD25 subsets for each marker). D, Percentage of CD127+ (open bars) or CD127+ (filled bars) CD4+ T cells that produced IFN-γ or IL-2 in response to 4 h stimulation with 50 ng/ml PMA + 500 ng/ml ionomycin (A23187). *, p < 0.05; **, p < 0.01 (Wilcoxon matched pairs test). E, Average fraction of CD4+ T cell subsets binding annexin V directly ex vivo (baseline) and after 48 h incubation. All experiments were conducted in peripheral blood samples obtained by venipuncture.*, p < 0.05; **, p < 0.01; ***, p < 0.001 (one-way ANOVA with Dunn’s multiple comparisons test).
FIGURE 3
FIGURE 3
The relative expansion of the CD127−CD25−CD4+ T cell subset is correlated with markers of disease progression. Correlations of the fractions of CD127−CD25− or CD127+CD25low/−CD4+ T cells with viral load (A), %CD4+ T cells (B), and absolute CD4+ T cell count (C) across a subset of HIV-infected individuals. Correlations were performed using the Spearman rank correlation coefficient test.
FIGURE 4
FIGURE 4
SIV infection of sooty mangabeys does not modulate the proportions of CD4+ T cell subsets defined by CD127 and CD25. Average fraction (left) and number per cubic millimeter of blood (right) of CD4+ T cells found in the CD127/CD25 subsets in peripheral blood of 110 SIV-infected (filled bars) and 30 uninfected (open bars) sooty mangabeys.
FIGURE 5
FIGURE 5
CD127−CD25−CD4+ T cells are not preferentially infected during chronic HIV infection. A, Quantification of cell-associated HIV DNA content using quantitative, real-time PCR within the CD127/CD25 subsets of CD4+ T cells expressed as copies of HIV gag per 10,000 cells (normalized by copies of albumin). Friedman’s test was used to measure statistical significance. B, Comparison of the average fraction of each CD127/CD25 CD4+ T cell subset expressing CCR5 in HIV-infected (filled bars) and uninfected (open bars) individuals.
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