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Dormant tumor cells resistant to ablative cancer therapy represent a significant clinical obstacle due to later relapse. Experimentally, the murine B cell lymphoma (BCL1) is used as a model of tumor dormancy in mice vaccinated with the BCL1 Ig. Here, we used this model to explore the cellular mechanisms underlying dormancy. Our previous studies have demonstrated that T cell-mediated immunity is an important component in the regulation of tumor dormancy because Id-immune T cells adoptively transferred into passively immunized SCID mice challenged with BCL1 cells significantly increased the incidence and duration of the dormant state. We have extended these observations and demonstrate that CD8+, but not CD4+, T cells are required for the maintenance of dormancy in BCL1 Ig-immunized BALB/c mice. In parallel studies, the transfer of Id-immune CD8+ cells, but not Id-immune CD4+ cells, conferred significant protection to SCID mice passively immunized with nonprotective levels of polyclonal anti-Id and then challenged with BCL1 cells. Furthermore, the ability of CD8+ T cells to induce a state of dormancy in passively immunized SCID mice was completely abrogated by treatment with neutralizing α-IFN-γ mAbs in vivo. In vitro studies demonstrated that IFN-γ alone or in combination with reagents to cross-link the surface Ig induced both cell cycle arrest and apoptosis in a BCL1 cell line. Collectively, these data demonstrate a role for CD8+ T cells via endogenous production of IFN-γ in collaboration with humoral immunity to both induce and maintain a state of tumor dormancy.

Soluble cytokine receptors (sCR) are generated in vivo through proteolytic cleavage of the membrane-bound receptors or by direct translation of mRNAs specifically encoding the soluble forms. Despite their widespread presence in biological fluids, the physiological role of endogenous sCR as immunoregulatory molecules is not yet well understood. In vivo, exogenous soluble interleukin-4 receptors (sIL-4R) have been shown to have both agonistic and antagonistic effects on IL-4 responses, depending on the relative concentration ratios of sIL-4R to IL-4. In an effort to elucidate the potential role of endogenous sIL-4R in the regulation of IL-4 responses, the mechanisms controlling the production of sIL-4R have been investigated. Although many cell types are able to constitutively produce low levels, production of sIL-4R is significantly up-regulated in vitro by T cell activation and IL-4. The ability of splenic cells to produce sIL-4R and the serum levels of sIL-4R have consistently been found to be increased during immune responses characterized by T cell activation and IL-4 secretion (Th2 responses). In agreement, clones of Th2, but not Th1, cells were found to significantly up-regulate sIL-4R production following antigenic stimulation. However, the production of sIL-4R by Th2 cells appears to be independent from that of IL-4 and can also be induced by cell contact and/or IL-1-dependent pathways. Taken together, these observations suggest that the production of sIL-4R in vivo is closely associated with the secretion of IL-4, and are consistent with the notion that endogenous sIL-4R are involved in the regulation of IL-4 activity during immune responses.

Extracorporeal Membrane Oxygenation (ECMO) is a life-saving procedure that provides short-term cardiac and respiratory support to people whose heart and lungs are dysfunctional. Growing use of ECMO has expanded the indications beyond acute severe respiratory and cardiac failure to include extracorporeal cardiopulmonary resuscitation and as a bridge for lung transplantation. Usage of ECMO within the pediatric population has seen a number of complications including an acute induction of systemic inflammatory response syndrome (SIRS) and long-term developmental neurological deficits, with an increasing number of children exhibiting neurological morbidities. We hypothesized that ECMO may potentiate the induction of a central nervous system (CNS)-targeting adaptive immune response which may lead to neurological injury. Using a single center prospective observational study, we sampled 20 pediatric ECMO patients and 5 aged-match disease control patients. Peripheral blood mononuclear cells were isolated using the Ficoll-Paque method and relative analysis revealed an increase in helper T-cells that correlated with ECMO treatment alone, while NK-T cells were found to be increased in the presence of CNS injury. Interestingly, we did see a decrease in activated peripheral T-helper cells (CD4+CD161+), and cytotoxic T cells (CD8+CD161+), which were preceded by an increase in activated macrophages (CD14 + CD11b + ) in ECMO treated patients. Only activated peripheral CD8 T-cells were found to associate with CNS injury. Using the CFSE recall response assay, we tested for CNS specificity by culturing cells with myelin basic protein (MBP), proteolipid lipoprotein (PLP), myelin oligodendrocyte glycoprotein (MOG), NMDA receptor GluN2A, and microtubule associated protein (MAP2) for 7 days and determined a response by measuring CFSE dilution and CD25 expression using flow cytometry. We observed an increased in myelin-targeting B-cells, myelin- and neuronal-targeting CD8 T-cells and no difference in autoreactive CD4 T-cells. In summary, ECMO induces a robust peripheral CNS-targeting adaptive immune response that may predispose a patient to long-term neurological injury.