Figure 2.

Pathways of human T cell activation in murine engraftment models. (A) Homeostatic proliferation occurs via two distinct processes, termed “slow” and “fast.” Slow proliferation (top panel) results from TCR stimulation by a weak agonist [e.g., autologous antigen-presenting cells (APCs) bearing self peptides] in the presence of IL-7, and does not require co-stimulatory ligands. Since murine IL-7 is recognized by human IL-7 receptors, this cytokine is likely to have high availability after transplantation into NSG mice. This pathway likely affects most of the transplanted human T cells. Fast proliferation (bottom panel) is driven by T cell receptor (TCR) recognition of high affinity antigens (e.g., microbial peptides from commensal species) in the presence of co-stimulatory ligands, and does not require IL-7. This process would likely only affect a subset of the transplanted T cells. (B) Xenogeneic activation may result from T cell recognition of murine peptides presented by self HLA molecules on human APCs (top panel), or by cross-reactivity of human TCRs for murine MHC molecules on murine APCs (bottom panel). Upregulation of co-stimulatory ligands by the human APCs or expression of cross-reactive co-stimulatory ligands by the murine APCs might be required for this pathway to induce productive activation, rather than anergy (which would be expected from TCR stimulation in the absence of co-stimulation). Xenogeneic activation pathways would be expected to affect only a subset of the transplanted human T cells.