TY - JOUR
T1 - Common gamma chain cytokines promote rapid in vitro expansion of allo-specific human CD8 + suppressor T cells
AU - Yu, Yuming
AU - Zitzner, Jennifer R.
AU - Houlihan, Josetta
AU - Herrera, Nancy
AU - Xu, Luting
AU - Miller, Joshua
AU - Mathew, James M.
AU - Tambur, Anat R.
AU - Luo, Xunrong
N1 - Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2011/12/14
Y1 - 2011/12/14
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0028948
DO - 10.1371/journal.pone.0028948
M3 - Article
C2 - 22194954
AN - SCOPUS:83355168683
VL - 6
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 12
M1 - e28948
ER -