T helper cell polarization in healthy people: implications for cardiovascular disease

Abstract

Atherosclerosis is a chronic inflammatory disease characterized by T lymphocyte infiltration into the atherosclerotic plaque. Assessments of T cell subtypes have demonstrated a predominance of CD4(+) T helper (Th) cells, implicated Th1 and Th17 immunity in both human and mouse atherogenesis, and provided some evidence suggesting protective roles of Th2 and T regulatory cells. Observations that certain inbred mouse strains have an inherent T helper bias suggest a genetic predisposition toward developing a particular T helper phenotype. This review summarizes our current understanding of mechanisms of antigen processing for major histocompatibility complex molecules, describes the different T helper cell subsets and their roles in atherosclerosis, and discusses mechanisms of genetic predisposition toward Th1/Th2 bias in mice. We also present data from our laboratory demonstrating inherent Th1/Th2 phenotypes in apparently healthy human volunteers that are stable over time and discuss the potential implications for cardiovascular disease.

Fig. 1

CD4⁺ T helper cell plasticity. Various lines of evidence in vitro and in vivo demonstrate plasticity between T helper subsets. Among the best characterized is the conversion of Tregs to IL-17 cells. In the presence of IL-6, Treg cells downregulate FoxP3 expression and convert to a Th17 phenotype. In the absence of TGF-β, both IL-23 and IL-12 promote differentiation of Th17 cells to interferon-γ (IFN-γ) producing Th1 cells. While TGF-β promotes the maintenance of Th17 cells, culturing these cells in the presence of TGF-β can also give rise to an “intermediate” subset that secrete both IFN-γ and IL-17. There is also evidence for the reprogramming of Th2 cells in response to type I and II interferons (IFNs) and interleukin-12 (IL-12), resulting in hybrid “Th2+1” cells that stably coexpress GATA-3 and T-bet and secrete both IL-4 and IFN-γ.

Fig. 2

Evaluation of T helper phenotypes in 28 apparently healthy men and women over an 18 month period. PBMCs were collected, activated in vitro with PMA, ionomycin, and brefeldin A, and measured by flow cytometry for (A) the % of CD4⁺ T cells positive for IFN-γ (CD4⁺IFN-γ⁺; Th1 cells), and (B) the % of CD4⁺ T cells positive for IL-4 (CD4⁺IL-4⁺; Th2 cells). (C) The ratio of %Th1/%Th2 cells was also evaluated. Each data point represents a single measurement in apparently healthy individuals collected over a period of 18 months. Data in this figure originally appeared in Sallam R, Bernstein I, Tracy RP. The Cellular Epidemiology of Inflammation: The Biochemical Indices of T Helper Cells are Stable Phenotypes Related to Plasma Markers of Inflammation, Adiposity, and Hormonal Status. EJBMB 26 (Supplement): 453–472 (2008).

Fig. 3

Associations of Th1 and Th2 phenotypes with secretion of IFN-γ and IL-4. (A) PBMCs were activated in vitro and measured by ELISA and chemiluminescence immunoassay for the secretion of (A) IFN-γ and (B) IL-4; the analytical coefficients of variation (CVs) were 6.0% and 8.2%, respectively. Each point represents a single measurement in apparently healthy volunteers over an 18 month period. The number of participants with IL-4 measurements varies to a small degree. The averaged analyte value of each volunteer was used to calculate Pearson correlation coefficients (r) of (C) %Th1 and IFN-γ and (D) %Th2 and IL-4. Data in this figure originally appeared in Sallam R, Bernstein I, Tracy RP. The Cellular Epidemiology of Inflammation: The Biochemical Indices of T Helper Cells are Stable Phenotypes Related to Plasma Markers of Inflammation, Adiposity, and Hormonal Status. EJBMB 26 (Supplement): 453–472 (2008).

Fig. 4

Quantitative immunoassay analyses of IgE and IgG_1–4 immunoglobulin subclasses. (A) Serum was assayed for IgE by chemiluminescence assay; the analytical CV was 5%. (B–E) IgG_1–4 subclasses were measured in plasma by immunochemical assay; analytical CVs were all <5%. Each point represents a single measurement collected over 18 months. Data in this figure originally appeared in Sallam R, Bernstein I, Tracy RP. The Cellular Epidemiology of Inflammation: The Biochemical Indices of T Helper Cells are Stable Phenotypes Related to Plasma Markers of Inflammation, Adiposity, and Hormonal Status. EJBMB 26 (Supplement): 453–472 (2008).