Abstract
Human CD8+ regulatory T cells, particularly the CD8+CD28− T suppressor cells, have emerged as an important modulator of alloimmunity. Understanding the conditions under which these cells are induced and/or expanded would greatly facilitate their application in future clinical trials. In the current study, we develop a novel strategy that combines common gamma chain (γc) cytokines IL-2, IL-7 and IL-15 and donor antigen presenting cells (APCs) to stimulate full HLA-mismatched allogeneic human CD8+ T cells which results in significant expansions of donor-specific CD8+CD28− T suppressor cells in vitro. The expanded CD8+CD28− T cells exhibit increased expressions of CTLA-4, FoxP3, and CD25, while down-regulate expressions of CD56, CD57, CD127, and perforin. Furthermore, these cells suppress proliferation of CD4+ T cells in a contact-dependent and cytokine-independent manner. Interestingly, the specificity of suppression is restricted by the donor HLA class I antigens but promiscuous to HLA class II antigens, providing a potential mechanism for linked suppression. Taken together, our results demonstrate a novel role for common γc cytokines in combination with donor APCs in the expansion of donor-specific CD8+CD28− T suppressor cells, and represent a robust strategy for in vitro generation of such cells for adoptive cellular immunotherapy in transplantation.
Highlights
Allogeneic organ transplantation has emerged as the current best therapeutic option for selected patients with end stage organ failure
Fresh CD8+ T cells were stimulated with human leukocyte antigen (HLA)-A, -B and -DR complete-mismatched antigen presenting cells (APCs) in the presence of IL-2 alone or a combination of cc cytokines IL-2, IL-7 and IL-15 as described in Materials and Methods [21]
Culture in the presence of a combination of cc cytokines IL-2, IL-7 and IL-15 significantly increased this population from 5.5% of all CD8+ cells on day 0 to 45.7% (51.5+/28.5%) on day 6, and 55.5% (58.5+/27.2%) on day 9 (Figure 1A), likely representing down-regulation of cell surface CD28 during the in vitro cell activation as previously described [26,27]
Summary
Allogeneic organ transplantation has emerged as the current best therapeutic option for selected patients with end stage organ failure. Regulatory T cell (Treg) based therapy has emerged as a promising means for immunomodulation to achieve transplant tolerance. Evidence suggests that CD8+ Tregs may play an important regulatory role in transplant tolerance [5,6,7,8], in addition to possible immunomodulatory roles in autoimmune disorders [9,10], cancers [11] and aging [12]. Induced CD8+ Tregs have been reported to bear various phenotypic characteristics, such as CD282, CD56+, CD57+, CTLA4+, CD103+, CD25+Foxp3+ or LAG3+CCL4+ [5,16,17,18,19].
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