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Reversing the motheaten phenotype
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Tumor-associated glycoproteins block CD4+ T cell surveillance
Although CD4+ T cells are important for optimal anti-tumor immunity, there is no information as to how tumors evade detection by them. Gutzmer et al. (p. 1023 ) looked at interference in immune surveillance by two tumor-associated Ags, the human type I integral membrane glycoprotein, GA733–2, and its mouse homologue, mEGP. Murine dendritic cells (DCs) transduced with an adenovirus vector expressing mEGP had a decreased ability to stimulate allogeneic CD4+ T cells in MLR compared with control DCs; their ability to respond to anti-CD3 Ab or Con A was not affected. Ag-specific T cells were unable to recognize mEGP-transduced DCs pulsed with the specific Ag or antigenic peptide. The inhibitory response was limited to Ags presented by MHC class II molecules, as mEGP-transduced DCs were able to stimulate T cell proliferation to Ags presented by MHC class I molecules. Similar results were found for human DCs transduced with a vector expressing GA733–2 and tested against primary CD4+ T cells from the same human donors. Mouse DCs exposed in vitro to homogenates of mEGP-transduced cells only, or containing a peptide presented by MHC class II molecules, lost general and specific CD4+ T cell stimulatory activities, respectively. Splenocytes from mice injected with DCs transduced with adenovirus-expressing mEGP had diminished in vitro T cell proliferative responses to adenovirus Ags compared with vector controls. The authors propose that mEGP and GA733–2 interference with MHC class II-dependent Ag presentation by DCs represents a novel mechanism of tumor evasion.
IL-21 regulation of cell-mediated tumor immunity
Activated CD4+ T cells produce IL-21 which shares the common 
-chain receptor subunit with IL-2 and IL-15 to influence CD8+ T cell responses. Moroz et al. (p. 900
) directly compared the effectiveness of these cytokines to promote survival of C57BL/6 (B6) mice injected with syngeneic thymoma cells expressing OVA Ag. Injection of IL-21 beginning 2 days after tumor injection led to 20–30% of the animals surviving greater than 120 days. Tumor-injected mice that received IL-2 or IL-15 survived to day 60 and day 80–90 compared with 40 days for untreated controls. The increased survival benefit was lost if IL-21 recipients had been depleted of CD8+ T cells; depletion of other cell types had no effect on survival. All IL-21-treated, long-term survivors also survived rechallenge with the same tumor but succumbed to challenge with an unrelated tumor. Significant numbers of CD8+ T cells were detected by OVA-tetramer staining at 45 days after tumor challenge only in the IL-21-treated group; highest lytic activity was seen at 30 days for CD8+ T cells from animals treated with IL-21 and IL-15. Adoptively transferred naive T cells expressing OVA were found in the peritoneal cavity of IL-21-treated mice 3–4 days after tumor challenge; IL-21 stimulated greater expansion and less apoptosis of these cells compared with IL-2. The results indicate that IL-21 enhances survival of mice to tumors by promoting longevity of activated tumor-specific CD8+ T cells.
Rap1 regulates oxidative stress in rheumatoid arthritis synovial T cells
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Stimulating B cells to kill
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and had greater tumoricidal activity than PBMCs stimulated by CpG-B ODN, that activate B cells. CpG-A ODN or IFN- induced expression of TRAIL/Apo-2L on PBMCs, including B cells. Purified TRAIL/Apo-2L-expressing B cells lysed tumor cells; addition of TRAIL-R2:Fc or IFN- neutralizing antiserum blocked the tumor cell lysis. TRAIL/Apo-2L expression was not induced by direct stimulation of purified B cells by CpG-A ODN. However, incubation of purified B cells with IFN- stimulated a modest level of TRAIL/Apo-2L expression that was enhanced by adding an agonist, CD40 mAb, with the IFN-. The authors conclude that IFN- produced by CpG ODN stimulation of PBMCs acts in concert with CD40-CD40L to induce B cells to kill tumor cells via a TRAIL/Apo-2L-dependent mechanism. Invariant NKT cells and infectious tolerance
Murine invariant NKT (iNKT) cells express an invariant TCR containing the V14 and J18 gene segments, recognize glycolipids in a CD1d-restricted manner and have been implicated in promoting peripheral T cell tolerance. Roelofs-Haarhuis et al. (p. 1043
) determined the role of iNKT cells in nickel (Ni)-induced tolerance. C57BL/6 (B6) wild-type mice and J18–/– B6 mice, that lack iNKT cells, were sensitized to Ni by intradermal injections. Both strains exhibited comparable levels of ear swelling when challenged by injection with Ni salts and H2O2. However, only B6 mice were tolerized by oral administration of Ni before sensitization and rechallenge. T cell-depleted spleen cells, but not splenic T cells, from J18–/– mice treated orally with Ni induced tolerance in B6 recipients after transfer. In contrast, splenic T cells, but not T cell-depleted spleen cells, from orally tolerized B6 donors transferred tolerance into naive J18–/– recipients. Infectious tolerance experiments showed that T cell-depleted spleen cells from orally treated J18–/– mice spread Ni tolerance to naive T cells in B6 recipient animals, and those B6 regulatory T cells, in turn, prevented sensitization of naive T cells when transferred into a second set of B6 recipients. No infectious tolerance was induced if the first recipients were J18–/– mice or if the donors were CD1–/–, IL-4–/–, or IL-10–/–. Moreover, tolerance in J18–/– mice could be induced by cotransfer of tolerogenic B6 T cell-depleted spleen cells and naive B6 spleen cells containing CD4+ T cells. The authors conclude that signals from iNKT cells are required for T cell-depleted spleen cells to generate regulatory T cells in this model of infectious tolerance to Ni.
Regulatory T cells and anti-melanoma responses
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when stimulated. The Treg cells inhibited the proliferation and cytokine production of stimulated CD4+CD25– T cells or CD8+ T cells; the suppressive activities were abolished by preventing cell contact via a transwell or by pretreatment of the Treg cells with anti-IL-10, anti-TGF-
1–3, or anti-CTLA-4 Abs. Only Treg cells from LNs with substantial tumor invasion produced immunosuppressive cytokines IL-10 and/or TGF-1 after stimulation. Immunoscope analyses indicated a highly diverse set of TCR V families among CD4+ T cells from metastatic and tumor-free LNs. The authors suggest that increased numbers of Treg cells in metastatic LNs down-regulate antitumor responses in melanoma patients, resulting in poor response to immunotherapy. Summaries written by Dorothy L. Buchhagen, Ph.D.
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