| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* James P. Wilmot Cancer Center,
Lymphoma Biology Program,
Department of Surgery, University of Rochester Medical Center, Rochester, NY 14642;
Department of Pathology, University of Arizona, Tucson, AZ 85724; and
¶ Department of Microbiology and Immunology, State University of New York, Buffalo, NY 14214
Regulatory T cells (TR) 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+ TR that are significantly overrepresented within FL nodes (FLN) compared with that seen in normal (nonmalignant, nonlymphoid hyperplastic) or reactive (nonmalignant, lymphoid hyperplastic) nodes. These TR actively suppress both the proliferation of autologous nodal CD8+CD25– and CD4+CD25– T cells, as well as cytokine production (IFN-
, TNF-
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 TR 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 TR are more suppressive than those derived from nonmalignant sources. Lastly, we demonstrate that inhibition of TGF-
signaling partially restores FLN T cell proliferation suggesting a mechanistic role for TGF- in FLN TR-mediated suppression.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by a Leukemia and Lymphoma Society Translational Research Grant, a James P. Wilmot Cancer Center Scholar Award, University of Rochester Human Immunology Core Pilot Project Grant 5-29712, and U.S. Public Health Service Grants R01-CA 10897 and R01-GM 65237.
2 Address correspondence and reprint requests to Dr. Steven H. Bernstein, Lymphoma Biology Program, James P. Wilmot Cancer Center, University of Rochester Medical Center, 601 Elmwood Avenue, Box 704, Rochester, NY 14642. E-mail address: Steven_Bernstein{at}urmc.rochester.edu
3 Abbreviations used in this paper: FL, follicular lymphoma; FLN, FL node; TR, regulatory T cell; GITR, glucocorticoid-induced TNFR-related protein; NLN, normal lymph node; RLN, reactive lymph node; rLAP, recombinant latency associated peptide of TGF-1; DLCL, diffuse large cell lymphoma; B-NHL, B non-Hodgkin’s lymphoma; PD.1, programmed death 1.
This article has been cited by other articles:
|
|
 |
|
  T. H. Schreiber The Use of FoxP3 as a Biomarker and Prognostic Factor for Malignant Human Tumors Cancer Epidemiol. Biomarkers Prev., October 1, 2007; 16(10): 1931 - 1934. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z.-Z. Yang, A. J. Novak, S. C. Ziesmer, T. E. Witzig, and S. M. Ansell CD70+ non-Hodgkin lymphoma B cells induce Foxp3 expression and regulatory function in intratumoral CD4+CD25 T cells Blood, October 1, 2007; 110(7): 2537 - 2544. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
