Abstract
HIV-1 infection rapidly leads to a loss of the proliferative response of memory CD4+ T lymphocytes, when cultured with recall antigens. We report here that CD73 expression defines a subset of resting memory CD4+ T cells in peripheral blood, which highly express the α-chain of the IL-7 receptor (CD127), but not CD38 or Ki-67, yet are highly proliferative in response to mitogen and recall antigens, and to IL-7, in vitro. These cells also preferentially express CCR5 and produce IL-2. We reasoned that CD73+ memory CD4+ T cells decrease very early in HIV-1 infection. Indeed, CD73+ memory CD4+ T cells comprised a median of 7.5% (interquartile range: 4.5–10.4%) of CD4+ T cells in peripheral blood from healthy adults, but were decreased in primary HIV-1 infection to a median of 3.7% (IQR: 2.6–6.4%; p = 0.002); and in chronic HIV-1 infection to 1.9% (IQR: 1.1–3%; p < 0.0001), and were not restored by antiretroviral therapy. Moreover, we found that a significant proportion of CD73+ memory CD4+ T cells were skewed to a gut-homing phenotype, expressing integrins α4 and β7, CXCR3, CCR6, CD161 and CD26. Accordingly, 20% of CD4+ T cells present in gut biopsies were CD73+. In HIV+ subjects, purified CD73+ resting memory CD4+ T cells in PBMC were infected with HIV-1 DNA, determined by real-time PCR, to the same level as for purified CD73-negative CD4+ T cells, both in untreated and treated subjects. Therefore, the proliferative CD73+ subset of memory CD4+ T cells is disproportionately reduced in HIV-1 infection, but, unexpectedly, their IL-7 dependent long-term resting phenotype suggests that residual infected cells in this subset may contribute significantly to the very long-lived HIV proviral DNA reservoir in treated subjects.
Highlights
CD73 belongs to the family of ectonucleotidases that hydrolyze extracellular nucleotides and are widely expressed multifunctional cell surface molecules, affecting the cellular milieu, providing products for cell signaling, and in some cases mediating cellular adhesion and migration [1]
From 76 healthy adult controls we found that CD73+CD45RO+ cells as a percent of peripheral blood CD4 T cells were quite variable, with a median of 7.5%
Since murine studies suggest that CD73 is involved in trafficking to lymph nodes [15,16], we studied whether CD73+ CD4+ T cells were found in normal lymph nodes, using ultrasoundguided lymph node fine needle biopsies of inguinal lymph nodes in healthy controls [23]
Summary
CD73 belongs to the family of ectonucleotidases that hydrolyze extracellular nucleotides and are widely expressed multifunctional cell surface molecules, affecting the cellular milieu, providing products for cell signaling, and in some cases mediating cellular adhesion and migration [1]. Murine CD4+ T regulatory cells (Tregs) express two ecto-nucleotidases, the ATPase CD39 and the ecto-50 -nucleotidase CD73 [2], such that their combined activity can sequentially catabolize ATP to ADP and AMP, and AMP to adenosine, respectively, and thereby suppress lymphocyte activation [2]. Tregs, using the CD25high CD127low FOXP3+ phenotype [3], it has been shown that a subset of human Tregs express CD39, and do not express CD73 [4,5,6,7]. It had previously been reported that ecto-50 -nucleotidase activity was reduced in PBMC in subjects with HIV-1 infection [9], and more recent studies have shown that human memory. CD73+ subset of CD4+ T cells, distinct from Tregs, was reduced in percentage, and in absolute number, in peripheral blood samples from HIV-infected subjects [6,10]. Decreases in CD73+ CD8+ T cells [6] and CD73+ B cells [11] have been reported in
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