CD28 regulates glucocorticoid-induced TNF receptor family-related gene expression on CD4+ T cells via IL-2-dependent mechanisms

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-γ, TNF-α 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-β signaling partially restores FLN T cell proliferation suggesting a mechanistic role for TGF-β in FLN TR-mediated suppression.

Section: Cells Infiltrate B-nhl Nodesmentioning

confidence: 99%

Section: And Cd4 ϩ Cd25 ϫ Nln and Normal Pb T Cellsmentioning

confidence: 99%

Follicular Lymphoma Intratumoral CD4+CD25+GITR+ Regulatory T Cells Potently Suppress CD3/CD28-Costimulated Autologous and Allogeneic CD8+CD25− and CD4+CD25− T Cells

Hilchey

Rimsza

et al. 2007

“…Regardless of the exact mechanism of action, T R cells are believed to contribute to the protective processes that govern susceptibility to, progression of, and remission from various autoimmune diseases. T R cells were described originally as CD4 ϩ T cells that coexpress CD25 and high levels of CD62L in naive mice and are now more appropriately characterized as CD4 Recent studies have revealed a functional role for CD25 expression on T R cells such that interruption of the IL-2R/IL-2 signaling pathway blocks T R effector function potentially via alterations in the expression of the glucocorticoid-induced TNFR-family gene (GITR or TNFRSF18) (4,5). Accordingly, a number of groups have targeted CD25 as a mechanism of depleting T R cells and studying resultant effects on T cell activation, trafficking, and/or effector function.…”

Section: D4mentioning

confidence: 99%

Cutting Edge: Anti-CD25 Monoclonal Antibody Injection Results in the Functional Inactivation, Not Depletion, of CD4+CD25+ T Regulatory Cells

Kohm

McMahon

Podojil

et al. 2006

Self Cite

290

226

CD4+CD25+ T regulatory (TR) cells are an important regulatory component of the adaptive immune system that limit autoreactive T cell responses in various models of autoimmunity. This knowledge was generated by previous studies from our lab and others using TR cell supplementation and depletion. Contrary to dogma, we report here that injection of anti-CD25 mAb results in the functional inactivation, not depletion, of TR cells, resulting in exacerbated autoimmune disease. Supporting this, mice receiving anti-CD25 mAb treatment display significantly lower numbers of CD4+CD25+ T cells but no change in the number of CD4+FoxP3+ TR cells. In addition, anti-CD25 mAb treatment fails to both reduce the number of Thy1.1+ congenic CD4+CD25+ TR cells or alter levels of CD25 mRNA expression in treatment recipients. Taken together, these findings have far-reaching implications for the interpretation of all previous studies forming conclusions about CD4+CD25+ TR cell depletion in vivo.

“…Furthermore, treatment of mice with anti-CD80 mAb during disease remission does not appear to affect CD11c ϩ DC Ag-presenting function. However, previous data from our laboratory showed that the addition of intact anti-CD80 mAb to naive CD4 ϩ CD62L ϩ T cells activated in the presence of Th1-promoting conditions induced an increase in the level of IFN-␥ produced (31). Therefore, an alternative hypothesis to explain exacerbation of clinical R-EAE disease following anti-CD80 FIGURE 6.…”

Section: Discussionmentioning

confidence: 82%

“…The present findings also strongly suggest that extreme caution must be taken when designing treatment regimens for autoimmune diseases such as MS based on Ab-mediated blockade of costimulatory molecules. Any treatment that has the potential to cross-link CD80 must be analyzed with the utmost care in that not only can cross-linking of CD80 on an APC affect cellular activity (8,31), but these same regimens may also positively regulate autoreactive CD4 ϩ T cell effector functions, thereby exacerbating disease.…”

Section: Discussionmentioning

confidence: 99%

CD4+ T Cell Expressed CD80 Regulates Central Nervous System Effector Function and Survival during Experimental Autoimmune Encephalomyelitis

Podojil

Kohm

Miller

2006

Self Cite

CD80 expressed on the surface of APCs provides a positive costimulatory signal to naive CD4+ T cells during activation. Therefore, it was hypothesized that treatment of SJL mice with various forms of anti-CD80 mAb during remission from the acute phase of relapsing experimental autoimmune encephalomyelitis (R-EAE) would ameliorate disease progression. We previously reported that treatment of SJL mice with anti-CD80 Fab during R-EAE remission blocked activation of T cells specific for endogenous myelin epitopes, inhibiting epitope spreading and clinical disease progression; however, treatment with the native form of the same anti-CD80 mAb exacerbated disease progression. The current data show that intact anti-CD80 mAb binds both CNS-infiltrating CD4+ T cells and CD11c+ dendritic cells and that exacerbation of R-EAE directly correlates with increased survival and activity of myelin-specific CD4+ T cells, while the percentage of CD11c+ dendritic cells in the CNS and their APC activity was not altered. In vitro data show that cross-linking CD80 on the surface of CD4+ T cells activated in the presence of Th1-promoting cytokines increases the level of T cell activation, effector function, and survival by directly up-regulating the expression levels of transcripts for T-bet, IFN-γ, and Bcl-xL. These findings indicate a novel regulatory role for CD80-mediated intracellular signals in CD4+ T cells and have important implications for using anti-costimulatory molecule mAb therapy in established autoimmune disease.