Activated memory CD4(+) T helper cells repopulate the intestine early following antiretroviral therapy of simian immunodeficiency virus-infected rhesus macaques but exhibit a decreased potential to produce interleukin-2 - PubMed (original) (raw)

Activated memory CD4(+) T helper cells repopulate the intestine early following antiretroviral therapy of simian immunodeficiency virus-infected rhesus macaques but exhibit a decreased potential to produce interleukin-2

J J Mattapallil et al. J Virol. 1999 Aug.

Abstract

Using the simian immunodeficiency virus (SIV)-infected rhesus macaque model, we performed a longitudinal study to determine the effect of antiretroviral therapy on the phenotype and functional potential of CD4(+) T cells repopulating intestinal mucosa in human immunodeficiency virus infection. Severe depletion of CD4(+) and CD4(+) CD8(+) T cells occurred in the intestinal mucosa during primary SIV infection. The majority of these cells were of activated memory phenotype. Phosphonate 9-[2-(phosphomethoxypropyl]adenine (PMPA) treatment led to a moderate suppression of intestinal viral loads and repopulation of intestinal mucosa by predominantly activated memory CD4(+) T-helper cells. This repopulation was independent of the level of viral suppression. Compared to preinfection values, the frequency of naive CD4(+) T cells increased following PMPA therapy, suggesting that new CD4(+) T cells were repopulating the intestinal mucosa. Repopulation by CD4(+) CD8(+) T cells was not observed in either jejunum or colon lamina propria. The majority of CD4(+) T cells repopulating the intestinal mucosa following PMPA therapy were CD29(hi) and CD11ahi. A subset of repopulating intestinal CD4(+) T cells expressed Ki-67 antigen, indicating that local proliferation may play a role in the repopulation process. Although the majority of repopulating CD4(+) T cells in the intestinal mucosa were functionally capable of providing B- and T-cell help, as evidenced by their expression of CD28, these CD4(+) T cells were found to have a reduced capacity to produce interleukin-2 (IL-2) compared to the potential of CD4(+) T cells prior to SIV infection. Persistent viral infection may play a role in suppressing the potential of repopulating CD4(+) T cells to produce IL-2. Hence, successful antiretroviral therapy should aim at complete suppression of viral loads in mucosal lymphoid tissues, such as intestinal mucosa.

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Figures

FIG. 1

FIG. 1

Differential expression of cell adhesion molecules (CD29, CD11a, and β7-integrin) on repopulating CD4+ T cells from intestinal mucosa compared to peripheral blood CD4+ T cells. The histograms show the differential expression of CD29 (VLA-4), CD11a (LFA-1), and β7-integrins on CD4+ T cells in jejunum and colon LPL and PBMC from uninfected rhesus macaques (solid line) and SIV-infected rhesus macaques after 4 weeks of PMPA therapy (broken line). Isolated cells were stained for CD4, CD29, CD11a, and β7-integrin and analyzed by flow cytometry. Analysis gates were set to include CD4+ T cells only to determine the relative fluorescence intensity of CD29, CD11a, and β7-integrin expression. Negative control samples were stained with matched isotype control antibodies.

FIG. 2

FIG. 2

Proliferation of intestinal CD4+ T cells following PMPA therapy. Cells isolated from jejunum and colon lamina propria after 4 weeks of PMPA therapy were stained for cell surface expression of CD4, fixed, permeabilized, and stained for the intracellular expression of Ki-67 antigen. Analysis gates were set to include CD4+ T cells only to determine the proportion of CD4+ Ki-67+ T cells. Negative control samples were stained with anti-CD4 antibody followed by intracellular labeling with matched isotype control antibody. PE, phycoerythrin; FITC, fluorescein isothiocyanate.

FIG. 3

FIG. 3

The CD4+ T cells repopulating the intestinal mucosa following PMPA therapy exhibited a decreased capacity to produce IL-2 compared to uninfected controls. The capacity of CD4+ T cells from jejunum and colon lamina propria and peripheral blood to produce IL-2 was determined following short-term in vitro stimulation with phorbol myristate acetate and ionomycin. Isolated cells were stained for cell surface expression of CD4, fixed, permeabilized, and stained for the intracellular production of IL-2. Analysis gates were set to include CD4+ T cells only to determine the capacity of CD4+ T cells to produce IL-2. Negative controls samples included cells stained with matched isotype control antibodies and cells stained with anti-CD4 antibody followed by intracellular labeling with matched isotype control antibody. PI, postinfection.

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