Description of CD8+ Regulatory T Lymphocytes and Their Specific Intervention in Graft-versus-Host and Infectious Diseases, Autoimmunity, and Cancer

Abstract

Gershon and Kondo described CD8⁺ Treg lymphocytes as the first ones with regulating activity due to their tolerance ability to foreign antigens and their capacity to inhibit the proliferation of other lymphocytes. Regardless, CD8⁺ Treg lymphocytes have not been fully described-unlike CD4⁺ Treg lymphocytes-because of their low numbers in blood and the lack of specific and accurate population markers. Still, these lymphocytes have been studied for the past 30 years, even after finding difficulties during investigations. As a result, studies have identified markers that define their subpopulations. This review is focused on the expression of cell membrane markers as CD25, CD122, CD103, CTLA-4, CD39, CD73, LAG-3, and FasL as well as soluble molecules such as FoxP3, IFN-γ, IL-10, TGF-β, IL-34, and IL-35, in addition to the lack of expression of cell activation markers such as CD28, CD127 CD45RC, and CD49d. This work also underlines the importance of identifying some of these markers in infections with several pathogens, autoimmunity, cancer, and graft-versus-host disease as a strategy in their prevention, monitoring, and cure.

Figure 1

CD8⁺ Treg lymphocyte. CD8⁺ Treg lymphocytes have different suppression mechanisms of cell activation and survival, using their own molecule expression: IL-2 receptor α-chain (CD25), IL-2 and IL-15 receptor β-chains (CD122), inhibitory receptor CD152 or CTLA-4, ectoenzymes CD39 and CD73 degrading ATP to ADP (CD39) and AMP to adenosine (CD73), an MHC-II-binding molecule called LAG-3 (lymphocyte activation gene-3), and the apoptosis-inducing molecule FasL. This T cell subset expresses low or absent costimulatory receptor CD28 and the IL-7 receptor α-chain (CD127), the cellular activation molecule CD45RC, and the integrin CD49d and releases cytokines as IL-10, IL-34, IL35, and IFN-γ; transcription factor FoxP3 inhibits IL-2 gene transcription. APC: antigen-presenting cell; CTLA-4: cytotoxic T-lymphocyte antigen 4.

Figure 2

Participation of CD8⁺ Treg lymphocytes in infectious diseases. In an infection with human immunodeficiency virus (HIV), CD8⁺ T lymphocyte has a phenotype CD28⁻CD127^loCD39⁺ inhibiting lymphocyte proliferation, which is probably related to the immunodeficiency shown during the disease. In a parasitic infection as leishmaniasis, the persistence of the parasite partly depends on the existence of CD8⁺ Treg lymphocytes expressing CTLA-4 and producing IL-10, which results in the prevalence of the disease. During immunosuppression situations, there is an increase in the population of IL-10-producing CD8⁺FoxP3⁺ Treg lymphocytes that inhibit CD4⁺ T cell proliferation, promoting infection by Epstein-Barr virus. The low protection of bacillus Calmette-Guérin vaccine is attributed factors as CD8⁺CD25⁺CD39⁺ Treg lymphocytes that inhibit the proliferation of CD4⁺ T lymphocytes producing Th1 cytokines as IFN-γ, necessary to activate other cell lines against mycobacteria.

Figure 3

Participation of CD8⁺ Treg lymphocytes in autoimmune diseases. During SLE, antibody production is eliminated thanks to the suppressive activity of TGF-β-producing CD8⁺CD25⁺FoxP3⁺ Treg lymphocytes, which are induced after an autologous transplant of hematopoietic progenitor cells, achieving the remission of the disease. On the other hand, during primary biliary cirrhosis, CD8⁺CD28⁻ T lymphocytes show decreased CD39 expression and fail to inhibit cell proliferation, promoting the severity of this autoimmune disease. In human multiple sclerosis, therapy with IFN-β regulates the immune system by reducing autoreactive T cell clones and increases CD8⁺CD25⁺CD28⁻ regulatory T cells. SLE: systemic lupus erythematosus.

Figure 4

Participation of CD8⁺ Treg lymphocytes in cancer. Regulatory T lymphocytes often aid in the evasion of the immune system by the cancer cell. Specifically, CD8⁺ Tregs can be induced in tumor tissue due to the presence of cytokines as GCS-F and IL-10. They can also be attracted to the tumor after the latter releases the chemokines CCL2 and CCL22 that attract regulatory lymphocytes expressing CCR2 and CCR4. In colorectal cancer, CD8⁺CD25⁺FoxP3⁺ Treg lymphocytes with an immunosuppressive phenotype characterized by expressing CTLA-4 and TGF-β inhibit Th1 lymphocyte proliferation. In prostate cancer, CD8⁺CD25⁺FoxP3⁺ Treg lymphocytes have been found to share markers with colorectal cancer and can inhibit naïve T lymphocyte proliferation.

Figure 5

Participation of CD8⁺ Treg lymphocytes in GVHD. After the remission of an oncohematologic disease, patients are treated with chemotherapy and radiotherapy. Later, they receive a hematopoietic stem cell graft from an HLA-compatible donor, at risk of developing GVHD that is characterized by being proinflammatory and producing IFN-γ and TNF-α. This response can be stopped by CD8⁺ Treg lymphocytes. When they encounter a plasmacytoid dendritic cell, lymphocytes are activated; they acquire phenotype LAG-3⁺FoxP3⁺CTLA-4⁺ and are able to suppress T lymphocyte allogeneic response via CTLA-4. If they are activated by a B lymphocyte, the CD8⁺ Tregs will express CD25⁺CTLA-4⁺FoxP3⁺, which suppresses cell proliferation and release of proinflammatory cytokines. The CD8⁺CD28⁻, a regulatory T cell subpopulation, play a critical role in in vitro and in posttransplantation allogeneic response. They can be generated by in vitro interaction with allogeneic peripheral blood mononuclear cells. Epitope presented in MHC-I is an alopeptide (allogeneic peptide) in all three Treg phenotypes.