The CD4+CD26− T-cell population in classical Hodgkin's lymphoma displays a distinctive regulatory T-cell profile

Abstract

Little is known about the gene expression profile and significance of the rosetting CD4 þ CD26À T cells in classical Hodgkin's lymphoma (cHL). To characterize these T cells, CD4 þ CD26À and CD4 þ CD26 þ T-cell populations were sorted from lymph node (LN) cell suspensions from nodular sclerosis HL (NSHL) and reactive LNs. mRNA profiles of stimulated and resting cell subsets were evaluated with quantitative RT-PCR for 46 genes. We observed a higher percentage of CD4 þ CD26À T cells in NSHL than in reactive LNs. The resting CD4 þ CD26À T cells in NSHL showed higher mRNA levels of CD25, CTLA4, OX40 and CCR4 compared with in LNs, supporting a regulatory T-cell (Treg) type, and this was validated by immunohistochemistry. Moreover, these cells showed low or no expression of the Th1-or Th2-related cytokines IL-2, IFN-g, IL-13, IL-12B, IL-4, and IL-5, and the chemoattractant receptor CRTH2. Besides Tregs, Th17 cells may exist in NSHL based on the significantly higher IL-17 mRNA level for both T-cell populations in NSHL. Upon stimulation in vitro, lack of upregulation of mRNA levels of most cytokine genes indicated an anergic character for the CD4 þ CD26À T-cell subset. Anergy fits with the Treg profile of these cells, probably explaining the immunosuppressive mechanism involved in NSHL.

Immunologic pathomechanism of Hodgkin's lymphoma

“…These cells do not express CCR3 that would link to RANTES and eotaxin from the microenvironment. CD4 þ CD26 À T cells are related to a specific set of T cells, producing IL-17 (Th17) [73]. PD-1 signaling has been reported to be upregulated in HL; HRS cells overexpress PD-1 ligand, which systemically arrests the exhausted T cell function by stimulating apoptosis of cytotoxic T cells and increases the number of immunosuppressive Tregs, resulting in tumor progression.…”

Rare association of Hodgkin lymphoma, Graves’ disease and myasthenia gravis complicated by post-radiation neurofibrosarcoma: coincidence or genetic susceptibility?

“…Some other diseases such as ITP, SCD can sometimes develop in HL patients that are in remission. In this case, it is probable (or at least may be suggested) that the development of diseases having an immune pathogenesis is based on permanent immune regulatory disorders (those of T reg cells) present in HL, even in cured cases [8,9]. Similarly, in the case of thyreoiditis or GD developing after RT of the neck region,-beside RT itself-a genetic immunological background is supposed to predispose someone for the appearance of autoantibodies [7].…”

Microenvironment, Crosstalk, and Immune Escape Mechanisms

“…The CD4+CD26− T cell subset in cHL has reduced mRNA levels of Th1-and Th2-associated cytokines in comparison to the CD4+CD26+ T cells from cHL and CD4+ T cells (both CD26− and CD26+) in reactive lymph nodes [ 12 ]. Based on much higher mRNA expression levels of IL-2RA (CD25), CCR4, FoxP3, CTLA4, TNFRSF4 (OX-40), and TNFRSF18 (GITR) observed in the CD4+CD26− T cells from cHL, it has been postulated that these cells have a Treg phenotype ( Fig.…”

“…Immunohistochemistry for several Treg-associated molecules demonstrates that the rosetting T cells in cHL express GITR, CCR4, and CD25, but not FoxP3. Scattered FoxP3-positive cells are present in the infi ltrate but only rarely in the direct vicinity of the HRS cells, and CTLA-4 shows a more diffuse presence [ 12 ]. Likewise, a small number of scattered IL-17-positive cells can be found in the reactive infi ltrate.…”

“…In addition, mildly enhanced IL-17 levels can be observed both in CD4+CD26− and CD4+CD26+ T cells from cHL in comparison to the T cells from the tonsil. Upon stimulation, the CD4+CD26− T cells fail to induce expression of cytokines, suggesting that the T cell population rosetting around the HRS cells or located in the direct vicinity of the HRS cells have an anergic phenotype [ 12 ]. Immunohistochemistry for several Treg-associated molecules demonstrates that the rosetting T cells in cHL express GITR, CCR4, and CD25, but not FoxP3.…”