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. 2010 May 24;5(5):e10788.
doi: 10.1371/journal.pone.0010788.

CD4+ T cell depletion, immune activation and increased production of regulatory T cells in the thymus of HIV-infected individuals

Alessandra Bandera  1 , Giulio Ferrario, Marina Saresella, Ivana Marventano, Alessandro Soria, Fabio Zanini, Francesca Sabbatini, Monica Airoldi, Giulia Marchetti, Fabio Franzetti, Daria Trabattoni, Mario Clerici, Andrea Gori
Affiliations

CD4+ T cell depletion, immune activation and increased production of regulatory T cells in the thymus of HIV-infected individuals

Alessandra Bandera et al. PLoS One. .

Abstract

Mechanisms by which HIV affects the thymus are multiple and only partially known, and the role of thymic dysfunction in HIV/AIDS immunopathogenesis remains poorly understood. To evaluate the effects of HIV infection on intra-thymic precursors of T cells in HIV-infected adults, we conducted a detailed immunophenotypic study of thymic tissue isolated from 7 HIV-infected and 10 HIV-negative adults who were to undergo heart surgery. We found that thymuses of HIV-infected individuals were characterized by a relative depletion of CD4+ single positive T cells and a corresponding enrichment of CD8+ single positive T cells. In addition, thymocytes derived from HIV-infected subjects showed increased levels of activated and proliferating cells. Our analysis also revealed a decreased expression of interleukin-7 receptor in early thymocytes from HIV-infected individuals, along with an increase in this same expression in mature double- and single-positive cells. Frequency of regulatory T cells (CD25+FoxP3+) was significantly increased in HIV-infected thymuses, particularly in priorly-committed CD4 single positive cells. Our data suggest that HIV infection is associated with a complex set of changes in the immunophenotype of thymocytes, including a reduction of intrathymic CD4+ T cell precursors, increased expression of activation markers, changes in the expression pattern of IL-7R and enrichment of T regulatory cells generation.

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Conflict of interest statement

Competing Interests: The present study was funded by a grant from Angelantoni Heraeus Scientific Instruments. The authors confirm that this does not alter their adherence to all the PloS ONE Policies on sharing data and materials.

Figures

Figure 1
Figure 1. Flow cytometry analysis of thymocytes.
Thymocytes were characterized by their forward (FSC) and side scattering (SSC) properties(A). Thymocytes were gated by their CD3+ expression and SSC characteristics (B) in CD3 High(gate F), CD3 low (gate G), CD3 neg (gate H). Dot plots CD3 High DP and SP (C) CD3 low DP (D) and CD3 neg TN and ISP (E) thymocytes are showed. DP = double positive; TN = triple negative; SP = single positive; ISP:immature single positive (CD4+).
Figure 2
Figure 2. Flow cytometry evaluation of thymopoietic stages in HIV-infected (grey triangles) and uninfected controls (white circles).
All thymopoietic stages were detected in both HIV+ and HIV- thymic tissues, but these stages were skewed in HIV-infected compared to uninfected thymuses. Thus, whereas the percentage of immature triple negative cells (CD3-CD4-CD8-, TN) and of immature single positive CD4+ cells (ISP4+) was comparable in HIV+ and in HIV- patients, an increase of CD3+CD4-CD8+ single positive (SP8+) cells (46.0% versus 22.5%) as well as a reduction of double-positive (DP) (CD3brightCD4+CD8+: 23.0% versus 31.05%) and CD3+CD4+CD8- single positive (SP4+) cells (13.9% versus 37.7%) were observed in HIV+ compared to HIV- subjects.
Figure 3
Figure 3. Expression of CD69, CD27 and Ki67 on thymocytes in HIV-infected (grey triangles) and uninfected controls (white circles).
HIV-infected subjects showed significantly higher percentages of CD69(a) expression in single positive CD8+ cells (HIV+ 7.9%; HIV- 0.6%; p = 0.02) compared to HIV-uninfected controls. A similar trend toward higher levels of CD27 (b) expression was seen in HIV-infected patients compared to HIV-negative subjects. This was observed in triple negative cells (HIV+ 6.0%; HIV- 0.625%, p = 0.05), in CD3+ double positive cells (HIV+ 4.7%; HIV- 1.25%), and in single positive cells (SP4+ HIV+ 10.2%, HIV- 1.0%; SP8+ HIV+11.0%, HIV-1.6%, p = 0.03). Significantly higher levels of Ki67 thymocytes (c) were detected in triple negative cells (HIV+ 39.5%, HIV- 17.2%, p = 0.04) and in double positive and CD8+ single positive cells of HIV-infected patients compared to uninfected controls (CD3+DP HIV+ 36.35%, HIV-11.45%, p = 0.04; SP4+ HIV+ 5.65%, HIV- 0.45%, p = 0.04; SP8+ HIV+ 15.9%, HIV- 1.15%, p = 0.02).
Figure 4
Figure 4. Expression of CD25 and FoxP3 on CD4+ SP and CD3+DP thymocytes in HIV-infected (grey triangles) and uninfected controls (white circles).
The expression of CD25 and FoxP3 on CD4+ SP cells was significantly increased in thymuses of HIV-infected individuals compared to uninfected controls (HIV+ 4.3%, HIV- 1.3%, p = 0.05), whereas the expression of CD25 and FoxP3 on CD4+CD8+ DP cells was comparable in the two groups of subjects (HIV+ 0.22%, HIV- 0.19%).
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