AbstractsMedical & Health Science

Functional immunity requires a balanced T cell immune response, which entails the maintenance of de novo production (i.e. TCR repertoire diversity) and the appropriate differentiation of effector subsets at the periphery. However, numerous pathogenic changes can perturb this homeostasis. On the one hand, diminished thymopoiesis or exhausted effectors cause immune dysfunction, leading to the persistence of virally infected or cancerous cells. Unrestrained immune reaction, on the other hand, can cause significant tissue damage. The main objective of my thesis therefore was to develop novel therapeutics to modulate T cell immunity in the context of cancer and inflammatory diseases. Interleukin-7 (IL7) is critically involved in T cell development and homeostatic proliferation. In order to pharmacologically induce T cell neogenesis for immune reconstitution and cancer therapy, we developed a novel biopharmaceutical based on the fusion of GMCSF and IL7 (GIFT7). GIFT7 administration in aged mice led to cortical hyperplasia, effectively reversing tissue involution. GIFT7-mediated hypertrophic effect includes an increase in total thymic cellularity and more importantly a 4-fold increase in the number of CD4-CD8-CD44intCD25-early thymic precursors. In the periphery, GIFT7 selectively expand a CD8+subset from pre-activated T cells with a phenotype defined as CD8+CD44+CD62L+CCR7+KLRG-CD27+, hereafter TGIFT7. The adoptive transfer of OTI-derived CD8 TGIFT7 into OVA-EG7-bearing mice leads to significant tumor regression. Furthermore, the human ortholog of GIFT7 (hGIFT7) leads to a two-fold increase in total cell number after 3 days and >80% of Ki67+expression in both CD4+ and CD8+ PBMC with concurrent reduction in PD1 expression, the cardinal marker of T cell exhaustion. Therapeutically, augmented T cell immunity via GIFT7 delivery rescues mice from disseminated leukemia. On the opposite spectrum of hypofunction, self-directed T cell over-reaction also demands therapeutic intervention. We have previously shown N-terminal modified(tetra-peptide-cleaved) MCP3 possessed immune suppressive activity. In view of this, we hypothesized that a synthetic cytokine linking GMCSF to MCP3 (GMME3) as part of a single polypeptide would augment its immune plasticity. We demonstrated that GMME3 induces significant Ca++ influx, activating IL10+CD21hiCD24hi CD1.dhi subset of splenic B cells (BGMME3) capable of inhibiting antigen presentation and Th17. The adoptive transfer of BGMME3 to mice symptomatic with experimental autoimmune encephalitis attenuated disease progression. Overall, the research presented in this thesis supports the use of GMCSF-based fusion cytokine as novel immune regenerative and modulatory therapeutics to (i)augment thymopoiesis, (ii) promote effector expansion, (iii) and regulate helper polarization. Therefore, our work points to the translational potential of fusion cytokines or fusion-primed immune cells as treatment of T cell dysfunction. L'immunité fonctionnelle des lymphocytes T exige le maintien de la diversité de…