Follicular lymphoma intratumoral CD4+CD25+GITR+ regulatory T cells potently suppress CD3/CD28-costimulated autologous and allogeneic CD8+CD25- and CD4+CD25- T cells.
Regulatory T cells (T(R)) play a critical role in the inhibition of self-reactive immune responses and as such have been implicated in the suppression of tumor-reactive effector T cells. In this study, we demonstrate that follicular lymphoma (FL)-infiltrating CD8+ and CD4+ T cells are hyporesponsive to CD3/CD28 costimulation. We further identify a population of FL-infiltrating CD4+CD25+GITR+ T(R) that are significantly overrepresented within FL nodes (FLN) compared with that seen in normal (nonmalignant, nonlymphoid hyperplastic) or reactive (nonmalignant, lymphoid hyperplastic) nodes. These T(R) actively suppress both the proliferation of autologous nodal CD8+CD25- and CD4+CD25- T cells, as well as cytokine production (IFN-gamma, TNF-alpha and IL-2), after CD3/CD28 costimulation. Removal of these cells in vitro by CD25+ magnetic bead depletion restores both the proliferation and cytokine production of the remaining T cells, demonstrating that FLN T cell hyporesponsiveness is reversible. In addition to suppressing autologous nodal T cells, these T(R) are also capable of suppressing the proliferation of allogeneic CD8+CD25- and CD4+CD25- T cells from normal lymph nodes as well as normal donor PBL, regardless of very robust stimulation of the target cells with plate-bound anti-CD3 and anti-CD28 Abs. The allogeneic suppression is not reciprocal, as equivalent numbers of CD25+FOXP3+ cells derived from either normal lymph nodes or PBL are not capable of suppressing allogeneic CD8+CD25- and CD4+CD25- T cells, suggesting that FLN T(R) are more suppressive than those derived from nonmalignant sources. Lastly, we demonstrate that inhibition of TGF-beta signaling partially restores FLN T cell proliferation suggesting a mechanistic role for TGF-beta in FLN T(R)-mediated suppression.
Hilchey
Shannon P
SP
James P. Wilmot Cancer Center, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.
De
Asit
A
Rimsza
Lisa M
LM
Bankert
Richard B
RB
Bernstein
Steven H
SH
D018106:CD28 Antigens / Q000032:analysis / Q000276:immunology*; D017252:CD3 Complex / Q000032:analysis / Q000276:immunology*; D015704:CD4 Antigens / Q000032:analysis; D002469:Cell Separation; D016207:Cytokines / Q000378:metabolism; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006801:Humans; D007108:Immune Tolerance; D007165:Immunosuppression Therapy; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000737:chemistry / Q000276:immunology*; D008224:Lymphoma, Follicular / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000819:agonists; D017475:Receptors, Nerve Growth Factor / Q000032:analysis; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis; D050378:T-Lymphocytes, Regulatory / Q000737:chemistry / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D018106:CD28 Antigens; D017252:CD3 Complex; D015704:CD4 Antigens; D016207:Cytokines; D053450:Glucocorticoid-Induced TNFR-Related Protein; D053645:Interleukin-2 Receptor alpha Subunit; D011948:Receptors, Antigen, T-Cell; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C491405:TNFRSF18 protein, human; D016212:Transforming Growth Factor beta