Regulatory T cells in Hodgkin lymphoma

The presence of an extensive lymphoid infiltrate distinguishes Hodgkin lymphoma (HL) from most other lymphomas. With respect to this infiltrate, a number of questions can be asked. The first one is what causes such an extensive infiltrate in the presence of only a few tumor cells. The explanation may well be that Reed-Sternberg cells produce and secrete high amounts of chemokines, in particular thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC), that attract cells expressing the CCR4 receptor, such as the T-helper 2 (Th2) lymphocyte.¹  Another important question is why there is no effective immune response against the tumor cells.

Marshall and colleagues (page 1755) confirm previous findings that the HL-infiltrating lymphocytes are anergic to stimulation with some mitogens and primary as well as recall antigens but also demonstrate that these cells suppress peripheral blood mononuclear cell (PBMC) responses. They identify the presence of interleukin-10 (IL-10)–secreting cells and CD4⁺CD25⁺ regulatory T cells. The immunosuppressive effect of the HL-infiltrating cells could be neutralized with anti–IL-10, by preventing cell-to-cell contact, and by anti–cytotoxic T-lymphocyte–associated antigen 4 (anti–CTLA-4).

Marshall and colleagues also conclude that the lymphocytes in HL do not produce cytokines, such as IL-2, IL-4, and interferon-γ (IFN-γ), with primary (keyhole limpet hemocyanin [KLH]) and recall (purified protein derivative [PPD]) antigens and the mitogen concanavalin A (ConA). However, in previous studies the lymphocytes were found to produce these cytokines when stimulated with phytohemagglutinin (PHA) or with phorbolester (PMA)–ionomycin. Specifically, when the CD26^– CD4 cells immediately surrounding the Reed-Sternberg cells were purified and stimulated with PMA ionomycin, they produced IL-4 and IFN-γ. The potential to produce IL-4 was the reason why these cells were previously considered Th2-like.²  The absence of IL-2 production upon stimulation is also associated with anergy. The exact nomenclature of these cells is thus a matter of semantics. In addition to the IL-10–producing cells (Tr1), there are also transforming growth factor β (TGF-β)–producing cells present in the infiltrate, and these have been termed Th3.

The findings by Marshall and colleagues indicate that there are variations in the populations involved in different cases. It can be concluded that, as an overall population, the infiltrating lymphocytes do not have Th1 type functions and are probably attracted into the tissues by chemokines TARC and MDC as CCR4-expressing Th2 cells. Although these cells do not spontaneously produce IL-2 or IL-4, they produce IL-10, despite not being fully activated, and therefore function as Tr1 cells.

The major remaining question is what causes the predominance of T cells with suppressor activity in Hodgkin lymphoma. It appears that Reed-Sternberg cells, although they have the genotype of B cells, execute a functional program that is similar to antigen-presenting cells but results in tolerance. Mechanisms include the production of immunosuppressive cytokines like IL-10, especially in Epstein-Barr virus–positive cases, and TGF-β, especially in nodular sclerosis cases, as well as the expression of FAS ligand that induces cell death in FAS-expressing activated T cells, while the Reed-Sternberg cells themselves are protected by overexpression of cFLIP (Fas-associating protein with death domain–like IL-1β–converting enzyme [FLICE]–inhibitory protein) or infrequently by FAS mutation.³ 

The relevance of these findings is that they may allow a better design of new treatment modalities. There are indications that the infiltrating cells in fact support the growth and survival of the Reed-Sternberg cells, and therefore blocking chemokines to prevent the influx of T cells may be effective. On the other hand, blocking of the immunosuppressive signals, such as IL-10 and TGF-β cytokines, or the removal of the suppressor regulatory T cells may enhance the effect of adoptive transfer of cytotoxic T cells.⁴