Are major histocompatibility complex molecules involved in the survival of naive CD4+ T cells?

The exact role of major histocompatibility complex (MHC) molecules in the peripheral survival of naive T cells is controversial, as some studies have suggested that they are critically required whereas others have suggested that they are not. Here we controlled for some of the features that differed among the earlier studies, and analyzed both the survival and expansion of naive CD4+ T cells transferred into MHC syngeneic, allogeneic, or MHC negative environments. We found that naive T cells transferred into MHC negative or allogeneic environments often fail to survive because of rejection and/or competition by natural killer (NK) cells, rather than failure to recognize a particular MHC allele. In the absence of NK cells, naive CD4+ T cells survived equally well regardless of the MHC type of the host. There was, however, an MHC requirement for extensive space-induced "homeostatic" expansion. Although the first few divisions occurred in the absence of MHC molecules, the cells did not continue to divide or transit to a CD44hi phenotype. Surprisingly, this MHC requirement could be satisfied by alleles other than the restricting haplotype. Therefore, space-induced expansion and survival are two different phenomena displaying different MHC requirements. Memory CD4+ T cells, whose survival and expansion showed no requirements for MHC molecules at all, dampened the space-induced expansion of naive cells, showing that the two populations are not independent in their requirements for peripheral niches.

Antigen-specific T-T interactions regulate CD4 T-cell expansion.

The regulation of CD4 T-cell numbers during an immune response should take account of the amount of antigen (Ag), the initial frequency of Ag-specific T cells, the mix of naive versus experienced cells, and (ideally) the diversity of the repertoire. Here we describe a novel mechanism of T-cell regulation that potentially deals with all of these parameters. We found that CD4 T cells establish a negative feedback loop by capturing their cognate major histocompatibility class (MHC)/peptide complexes from Ag-presenting cells and presenting them to Ag-experienced CD4 T cells, thereby inhibiting their recruitment into the response while allowing recruitment of naive T cells. The inhibition is Ag specific, begins at day 2 (long before Ag disappearance), and cannot be overcome by providing new Ag-loaded dendritic cells. In this way, CD4 T-cell proliferation is regulated in a functional relationship to the amount of Ag, while allowing naive T cells to generate repertoire variety.

Impact of imatinib on the pharmacokinetics and in vivo efficacy of etoposide and/or ifosfamide.

BACKGROUND: Using a human small cell lung cancer (SCLC) xenografted in nude mice, we have previously reported enhanced tumor growth inhibition following chemotherapy in combination with imatinib (STI571). We therefore investigated the in vivo impact of imatinib on the pharmacokinetics and efficacy of chemotherapy. METHODS: Two different human tumors were used: SCLC6 small cell lung cancer xenografted in nude mice, and LY-3 EBV-associated human B-cell lymphoma xenografted in SCID mice. Plasma, urine, and fecal concentrations of etoposide (VP16) were determined by a validated high performance liquid chromatography method. Plasma concentrations of ifosfamidewere determined by a validated gas chromatography assay with nitrogen-phosphorus detection. RESULTS: Slight tumor growth inhibition was induced by imatinib administered alone in one in vivo EBV-associated B-cell lymphomatous xenograft. In contrast, an increase of the chemotherapy-induced antitumor effect was observed in the lymphoma model but not in a small cell lung cancer model when mice bearing human xenografted tumors were treated concomitantly by imatinib and chemotherapy. This antitumor effect was not influenced by concomitant administration of fluconazole. The AUC0-3 h (Area Under the concentration-time Curve) of etoposide was increased when mice were treated with etoposide + imatinib due to decreased fecal excretion. In contrast, imatinib did not appear to influence the urinary excretion of etoposide, and concomitant administration of the CYP3A4 inhibitor, fluconazole, with imatinib did not modify the pharmacokinetics of etoposide plus imatinib alone. CONCLUSION: Altogether, these results therefore justify further prospective phase I and II clinical trials with combinations of etoposide-based chemotherapy and imatinib in patients with certain cancers, such as malignant lymphoma, with careful toxicologic monitoring.

Imatinib mesylate reduces rituximab-induced tumor-growth inhibition in vivo on Epstein-Barr virus-associated human B-cell lymphoma.

We have reported earlier an increase of tumor-growth inhibition following chemotherapy combined with concomitant administration of imatinib mesylate. Conversely, the combination of imatinib and rituximab has been reported in very few cases of patients and remains controversial. To explore this particular combination of targeted therapies, we therefore investigated the in-vivo impact of rituximab plus imatinib on B-cell lymphoproliferation. Combination of the tyrosine kinase inhibitor imatinib mesylate (STI571) and the anti-CD20 monoclonal antibody rituximab was evaluated on an Epstein-Barr virus-associated B-cell lymphoproliferative disorder xenografted into severe combined immunodeficient or Rag2/gammac-/- (B-, T- and NK-) mice. Using severe combined immunodeficient mice, we found that STI571 diminished the efficacy of rituximab to inhibit tumor growth in vivo. Using alymphoid Rag2/gammac-/- mice, we showed that the effect of STI571 was not dependent on the presence of natural killer cells. In contrast, serum complement administered after STI571 treatment reversed this inhibitory effect. Finally, using nonimmunodeficient mice, we observed an in-vivo decrease of CD4-positive T-cells and mature B-cell lymphocytes after imatinib administration. We found that STI571 decreased the in-vivo efficacy of rituximab via serum protein components that could influence complement-dependent cytotoxicity. In contrast, this effect was not dependent on the presence of natural killer cells.

Dendritic cell maturation controls adhesion, synapse formation, and the duration of the interactions with naive T lymphocytes.

The initiation of adaptive immune responses requires the direct interaction of dendritic cells (DCs) with naive T lymphocytes. It is well established that the maturation state of DCs has a critical impact on the outcome of the response. We show here that mature DCs form stable conjugates with naive T cells and induce the formation of organized immune synapses. Immature DCs, in contrast, form few stable conjugates with no organized immune synapses. A dynamic analysis revealed that mature DCs can form long-lasting interactions with naive T cells, even in the absence of Ag. Immature DCs, in contrast, established only short intermittent contacts, suggesting that the premature termination of the interaction prevents the formation of organized immune synapses and full T cell activation.