Dynamics of cytokine/chemokine responses in intestinal CD4+ and CD8+ T Cells during Acute Simian Immunodeficiency Virus Infection

Abstract

Loss of intestinal CD4(+) T cells was associated with decreased production of several T-helper 1 (TH1) and TH2 cytokines and increased production of interleukin 17 (IL-17), gamma interferon (IFN-γ), CCL4, and granulocyte-macrophage colony-stimulating factor (GM-CSF) by CD8(+) T cells 21 days after simian immunodeficiency virus (SIV) infection in rhesus macaques. Shifting of mucosal TH1 to TH2 or T-cytotoxic 1 (TC1) to TC2 cytokine profiles was not evident. Additionally, both CD4(+) and CD8(+) T cells showed upregulation of macrophage migration inhibition factor (MIF) and basic fibroblast growth factor (FGF-basic) cytokines that have been linked to HIV disease progression.

Fig 1

Distribution of single-positive (SP) CD4⁺ CD8⁺ and double-positive (DP) CD4⁺ CD8⁺ T cells in jejunum LPLs and their expression of phenotypic markers of activation and exhaustion. (A) Representative contour plots showing SP CD4⁺, CD8⁺, and DP CD4⁺ CD8⁺ T-cell population before and 21 days after SIV infection. Plots were generated by gating CD3⁺ T cells. (B) Mean percentages (± standard errors [SE]) of SP CD4⁺, CD8⁺, and DP CD4⁺ CD8⁺ T cells of five SIV_MAC251-infected macaques before infection (pre) and 21 days after infection (post). Representative contour plots show PD-1 (C) and CD38 (E) phenotypic expression in SP CD4⁺ and SP CD8⁺ T-cell population before and after SIV infection, where cells were gated through CD3⁺ T cells. Mean percentages (± SE) of T-cell exhaustion (PD-1) (D) and activation (CD38) (F) markers are shown for SP CD4⁺ and CD8⁺ T cells of five SIV_MAC251-infected macaques before and after SIV infection. Asterisks indicate statistically significant differences in respective cell populations, compared to preinfection levels (P < 0.05). FSC, forward-angle light scatter.

Fig 2

Cytokine/chemokine profile in jejunum CD3⁺ CD4⁺ T cells during acute SIV_MAC251 infection. Bar graphs show 18 different cytokine/chemokine measurements taken before and 21 days (21d) after SIV infection from culture supernatants of sorted single-positive CD4⁺ T cells stimulated with either anti-CD3/CD28 monoclonal antibodies or Staphylococcus enterotoxin B (SEB). Medium control values were subtracted from all values before the analysis (n = 5). The number and arrow in each bar for the postinfection time point show the mean fold increase (upward arrow) or decrease (downward arrow) compared to the preinfection level.

Fig 3

Cytokine/chemokine profile in jejunum CD3⁺ CD8⁺ T cells during acute SIV_MAC251 infection. Bar graphs show 18 different cytokine/chemokine measurements taken before and 21 days (21d) after SIV infection from culture supernatants of sorted single-positive CD8⁺ T cells stimulated with either anti-CD3/CD28 monoclonal antibodies or Staphylococcus enterotoxin B (SEB). Medium control values were subtracted from all values before the analysis (n = 5). The number and arrow in each bar for the postinfection time point show the mean fold increase (upward arrow) or decrease (downward arrow) compared to the preinfection level.

Fig 4

Relative contribution of cytokine/chemokine expression during acute SIV_MAC251 infection. The pie charts illustrate the relative percentage contribution of each cytokine/chemokine from culture supernatants of sorted single-positive CD4⁺ and CD8⁺ T cells stimulated with anti-CD3/CD28 monoclonal antibodies before and 21 days after SIV infection. Medium control values were subtracted from all values before the analysis (n = 5). Note that cytokines having 0.01 to 0.04% overall contribution are represented as 0% in the pie chart.