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Abstract: Cytotoxic T lymphocytes (CTLs) play a dominant role in the pathogenesis of autoimmune diabetes, commonly denoted Type 1 Diabetes (T1D). These CTLs (notably T cells) recognize and kill insulin-secreting pancreatic cells, reducing their number by . The resulting reduction of insulin secretion causes the defective regulation of glucose metabolism, leading to the characteristic symptoms of diabetes. Recognition of cells as targets by CTLs depends on the interactions between MHC-peptide complexes on the surface of cells and receptors (TCRs) on T cells. Those CTLs with high affinity TCRs (also called high avidity T cells) cause most of the harm, while those with low affinity TCRs (also called low avidity T cells) play a more mysterious role. Recent experimental evidence suggests that low avidity T cells accumulate as memory T cells during the disease and may be protective in NOD mice (a strain prone to developing T1D), delaying disease progression. It has been hypothesized that such low avidity T cells afford disease protection either by crowding the islets of Langerhans, where cells reside, or by killing antigen presenting cells (APCs). In this paper, we explore the hypothesized mechanisms for this protective effect in the context of a series of models for (1) the interactions of low and high avidity T cells, (2) the effect of APCs and (3) the feedback from cell killing to autoantigen-induced T cell proliferation. We analyze properties of these models, noting consistency of predictions with observed behaviour. We then use the models to examine the influence of various treatment strategies on the progression of the disease. The model reveals that progressive accumulation of memory low avidity autoreactive T cells during disease progression makes treatments aimed at expanding these protective T cell types more effective close to, or at the onset of clinical disease. It also provides evidence for the hypothesis that low avidity T cells kill APCs (rather than the alternate hypothesis that they crowd the islets). [Copyright &y& Elsevier]

Abstract: In this paper, we focus our attention on the relevance of HLA-G in cancer in the light of our recent advances on the expression and immunological function of HLA-G. Regarding HLA-G function, we recently showed that in addition to its direct inhibitory effects on T, APC and NK function, HLA-G induces suppressor cells via two distinct processes: (i) either by cell differentiation of naïve T cells into lasting suppressor T cells or (ii) by rapid transfer of HLA-G from APC or tumor cells to T or NK cells converting them into temporary HLA-G-positive suppressor cells. Regarding HLA-G expression, we described that tumor-microenvironment factors such as hypoxia, IDO and, TNF-α regulate the expression of HLA-G by tumor cells in a way that favors tumor escape from NK lysis. These findings reinforce the role of HLA-G as one mechanism of tumor-driven immune evasion and provide potential targets for testing novel anticancer treatment strategies. [Copyright &y& Elsevier]

Abstract: Signaling pathways such as the pre-TCR and Wnt pathways regulate α/β T cell differentiation in thymus. Mice lacking an essential component of the pre-TCR exhibit arrest at the (CD4−CD8−) (CD44−CD25+) stage (DN3) of thymocyte development, and introduction of p53 deficiency into those mice abrogates this arrest, resulting in transition to the (CD4+CD8+) double-positive (DP) stage. This paper examines the effect of inactivation of p53 on thymocyte development in Bcl11b−/− mice that exhibit arrest at the DN3 or (CD4−CD8+) immature single-positive (ISP) stage. No DP thymocytes were detected in thymocytes of adoptive transfer experiments in scid mice that were derived from p53−/−Bcl11b−/− precursors but ISP thymocytes increased in the proportion and in the cell number approximately three times higher than those from Bcl11b−/− precursors. Consistently, the level of apoptosis decreased to the level of wild-type precursors. These results suggest that inactivation of p53 is sufficient for DN3 thymocytes to differentiate into the ISP, but not to DP, stage of thymocyte development in Bcl11b−/− mice. This provides evidence for a novel p53-mediated checkpoint that regulates the transition from the DN3 to ISP stage of thymocyte development. [Copyright &y& Elsevier]

In this paper, we propose and analyse a mathematical model for chronic myelogenous leukemia (CML), a cancer of the blood. We model the interaction between naive T cells, effector T cells, and CML cancer cells in the body, using a system of ordinary differential equations which gives rates of change of the three cell populations. One of the difficulties in modeling CML is the scarcity of experimental data which can be used to estimate parameters values. To compensate for the resulting uncertainties, we use Latin hypercube sampling (LHS) on large ranges of possible parameter values in our analysis. A major goal of this work is the determination of parameters which play a critical role in remission or clearance of the cancer in the model. Our analysis examines 12 parameters, and identifies two of these, the growth and death rates of CML, as critical to the outcome of the system. Our results indicate that the most promising research avenues for treatments of CML should be those that affect these two significant parameters (CML growth and death rates), while altering the other parameters should have little effect on the outcome. [Copyright &y& Elsevier]