T-Cell Depletion in the Colonic Mucosa of Patients With Idiopathic CD4+ Lymphopenia

Abstract

Idiopathic CD4(+) lymphopenia (ICL) is a rare syndrome characterized by low peripheral CD4(+) T-cell counts that can lead to serious opportunistic infections. The pathogenesis of ICL remains unclear, and whether effector sites are also lymphopenic is unknown. In this study, rectosigmoid mucosal biopsy specimens from patients with ICL and healthy controls were evaluated. Significant T-cell lymphopenia was observed in the mucosal tissue of patients with ICL by flow cytometry and immunohistochemistry, compared with healthy controls. Functional capacity of T cells, assessed by production of interferon γ and interleukin 17, was preserved in the mucosa of patients with ICL. In contrast to T lymphocytes, the frequency of myeloid cells (neutrophils and macrophages) was elevated in the colonic mucosa of patients with ICL. Despite the observed mucosal abnormalities, plasma levels of intestinal fatty acid binding protein, a marker of enterocyte turnover and other inflammatory biomarkers, including interleukin 6, C-reactive protein, and tumor necrosis factor, were not elevated in patients with ICL, compared with healthy controls, whereas soluble CD14 levels were minimally elevated. These data suggest that patients with ICL, despite gut mucosal lymphopenia and local tissue inflammation, have preserved enterocyte turnover and T-helper type 17 cells with minimal systemic inflammation. These observations highlight differences from patients with human immunodeficiency virus infection, with or without AIDS, and may partially explain their distinct clinical prognosis.

Keywords: HIV/AIDS; biomarkers; idiopathic CD4+ lymphopenia; inflammation; mucosal immunity.

Figure 1.

Patients with idiopathic CD4⁺ lymphopenia (ICL) are lymphopenic in the colon. Number of lymphocytes found in rectosigmoid tissue specimens from patients with ICL (blue circles) and healthy controls (HCs; red squares). A and B, Results of immunohistochemical analysis, showing the percentage of the area stained for CD3, CD4, or CD8 (A), with an example of CD4 staining in the lamina propria shown in a patient with ICL and a HC in (B). C, Results of flow cytometry, showing the number of CD3⁺, CD4⁺, CD8⁺, or DN (defined as CD3⁺CD4⁻CD8⁻) cells per gram of tissue. Bars represent median values with interquartile ranges. P values are for comparisons between patients with ICL and HCs by the Mann–Whitney U test.

Figure 2.

Contrary to peripheral blood, the rectosigmoid mucosa of patients with idiopathic CD4⁺ lymphopenia (ICL) had proportions of CD4⁺, CD8⁺, and DN lymphocytes within the CD3⁺ population that were similar to those for healthy controls (HCs). A–C, Percentages of CD4⁺ T cells (A), CD8⁺ T cells (B), and CD3⁺CD4⁻CD8⁻ (DN) lymphocytes (C) among the CD3⁺ cells found in peripheral blood lymphocytes (PBLs) or rectosigmoid tissue (colon) specimens from patient with ICL (blue circles) and HCs (red squares). D, Median percentages of CD4⁺, CD8⁺, and DN lymphocytes among the CD3⁺ lymphocytes found in PBLs and colon from the individual samples represented in panels A–C. Bars represent median values with interquartile ranges. P values are for comparisons between patients with ICL and HCs by the Mann–Whitney U test. Abbreviations: NS, not significant; PB, peripheral blood.

Figure 3.

CD4⁺ T cells in the colon of patients with idiopathic CD4⁺ lymphopenia (ICL) are functional. Proportion of mucosal CD4⁺ T cells producing interleukin 17 (IL-17; A) or interferon γ (INF-γ; B) after mitogenic stimulation. P values represent comparisons of the 2 groups by the Mann–Whitney U test. Bars are median values with interquartile ranges. Abbreviation: HC, healthy control.

Figure 4.

Patients with idiopathic CD4⁺ lymphopenia (ICL) have increased numbers of myeloid cells in the lamina propria of the colon. Macrophages (A) or polymorphonuclear cells (PMNs; B) underwent immunohistochemical (IHC) staining and were quantified as the percentage of the surface area stained. Bars represent median values with interquartile ranges. P values are for comparisons between patients with ICL and healthy controls (HCs) by the Mann–Whitney U test.

Figure 5.

The increased level of soluble CD14 (sCD14) in patients with idiopathic CD4⁺ lymphopenia (ICL) is not explained by epithelial cell damage and/or microbial translocation. Plasma concentrations of intestinal fatty acid–binding protein (I-FABP; A) and sCD14 (B) in 32 patients with ICL (blue circles) and 28 healthy controls (HCs; red squares). P values represent comparisons of the 2 groups by the Mann–Whitney U test. Bars represent median values with interquartile ranges.