Regulatory T-cells in chronic lymphocytic leukemia and autoimmune diseases

Abstract

Regulatory T-cells (Tregs) constitute a small subset of cells that are actively involved in maintaining self-tolerance, in immune homeostasis and in antitumor immunity. They are thought to play a significant role in the progression of cancer and are generally increased in patient with chronic lymphocytic leukemia (CLL). Their number correlates with more aggressive disease status and is predictive of the time to treatment, as well. Moreover, it is now clear that dysregulation in Tregs cell frequency and/or function may result in a plethora of autoimmune diseases, including multiple sclerosis, type 1 diabetes mellitus, myasthenia gravis, systemic lupus erythematosus, autoimmune lymphoproliferative disorders, rheumatoid arthritis, and psoriasis. Efforts are made aiming to develop approaches to deplete Tregs or inhibit their function in cancer and autoimmune disorders, as well.

Figure 1

Flow cytometric detection of Tregs. Tregs are CD4+ lymphocytes displaying a CD45 expression of T-cell subpopulations (A). CD25 antigen is expressed at high density whereas CD127 at low to undetectable levels (B and C).Selected CD25+/CD127+ lymphocytes are positive for CD45RO (D).

Figure 2

Regulatory T-cells: development and subsets. Three major subjects of Tregs have been recognized so far. A) Tregs (innate and adaptative): they express CD25, FoxP3, CTLA-4, αβ-TCR, and secrete the immunosuppressive lymphokines IL-10 and TGF-β. B) Tr1 cells: they do not express FoxP3 nor large amount of CD25, secrete IL-10 and TGF-β. Tr1 cells are abundant in the intestine where they elicit their main function that is making tolerance to the many agents that are part of its diet. C) Th₃ cells: they are also prevalent in the intestine and like to Tr1 cells act suppressing immune responses to ingested antigens (oral tolerance) by means of TGF-β secretion.

Figure 3

ROC curve graphically showing the trade-offs between sensitivity and specificity for different cutoffs used to discriminate between positive and negative cases (i.e., treatment demand vs no treatment demand patients). The best predictive cutoff of circulating Treg cell number seems to be in the range from ≥40 to ≥42/μL. The result of cutoff ≥41/μL shows the best predictive power among the others.

Figure 4

Circulating Tregs number in healthy subjects, MBL and CLL patients grouped according to Rai/Binet clinical stages. Data are expressed as mean absolute circulating Tregs number (/μL) ± standard deviations.