Abstract Cancers and autoimmune diseases, which affect 1.6% and 4.9% of the U.S. population respectively, are often treated with chemotherapy and immunosuppressive drugs with variable response rates. One alternative treatment option are hematopoietic stem cell (HSC) transplantations. Unfortunately, the biology behind these transplants remains unclear despite being in practice for over 60 years. Our research aims to use a humanized mouse model to understand the different molecular mechanisms that lead to acute GVHD, hematopoietic recovery/rejection and GVL. Here, we will focus on our data recapitulating clinical GVHD in different graft sources. Injecting equivalent numbers (2E7) of bone marrow (BM) mononuclear cells and G-CSF mobilized (MB) mononuclear cells into non-irradiated NSG mice results in 50% & 0% penetrance of GVHD respectively at 12 weeks. Concurrently, we have measured the Tc proliferation and IFNγ secretion in these mice over the course of 12 weeks that reveals an elevated activation status in BM Tc’s from an early stage. Interestingly, stimulating the Tc’s directly in vitro results in equivalent activation potentials suggesting a prominent role of myeloid cells in the induction of GVHD and not Tc’s. The following investigations have shown an increased expression of the B7 complex on BM myeloid cells and an increase in their IL-6 secretion. These early observations suggest that the “accessory cells” injected from the different HSC grafts are vastly important for driving clinical outcomes. Understanding the molecular cross-talk between the “accessory” cells and the underlying cellular differences attributed to each HSC source will better inform clinicians on the best treatment practices for patients.