Cutting Edge: Recent Immune Status Determines the Source of Antigens That Drive Homeostatic T Cell Expansion

Abstract

Homeostatic proliferation of naive T cells transferred to T cell-deficient syngeneic mice is driven by low-affinity self-MHC/peptide ligands and the cytokine IL-7. In addition to homeostatic proliferation, a subset of naive T cells undergoes massive proliferation in chronically immunodeficient hosts, but not in irradiated normal hosts. Such rapid T cell proliferation occurs largely independent of homeostatic factors, because it was apparent in the absence of IL-7 and in T cell-sufficient hosts devoid of functional T cell immunity. Strikingly, immunodeficient mice raised under germfree conditions supported only slow homeostatic proliferation, but not the marked T cell proliferation observed in conventionally raised immunodeficient mice. Thus, polyclonal naive T cell expansion in T cell-deficient hosts can be driven predominantly by either self-Ags or foreign Ags depending on the host’s previous state of T cell immunocompetency.

Increased intensity lymphodepletion and adoptive immunotherapy—how far can we go?

“…In the gastrointestinal tract TBI causes mucosal damage, leading to bacterial translocation and release of lipopolysaccharide, which might act via Toll-like receptors, further enhancing the function of APCs and promoting T-cell activation and expansion. 65,66,67 Developing a safe lymphodepleting regimen for future trials Nonmyeloablative lymphodepleting preconditioning with cyclophosphamide and fludarabine illustrated the importance of reducing the host lymphocyte pool prior to adoptive transfer of TILs. 17 The above-described animal data may give a compelling reason to investigate a truly 'lymphomyeloablative' TBI-based regimen as a basis for further enhancement of ACT therapy.…”

CD64 distinguishes macrophages from dendritic cells in the gut and reveals the Th1‐inducing role of mesenteric lymph node macrophages during colitis

“…8B, are responsible for the induction of colitis when transferred in the absence of Treg cells. Antigenic peptides derived from the enteric bacteria and presented by MHCII molecules have been shown to be responsible for this TCR-driven fast proliferation whereas the slow proliferation is independent of MHCII molecules and IL-7-driven [26][27][28][29][30]. We took advantage of this model to determine whether upon transfer into Cd3e 5/ 5 x MHCII / mice, MLN-resident inflammatory M s isolated from MHCII-sufficient, colitic mice were capable of rescuing the fast proliferation of cotransferred CD4 + T cells and their differentiation into IFN-γ-producing effectors.…”

Homeostatic Proliferation of Naive CD4+ T Cells in Mesenteric Lymph Nodes Generates Gut-Tropic Th17 Cells

“…Because the homeostatic proliferation of donor T N cells supplies a memory-phenotype T cell pool (40)(41)(42)(43)(44)(45), this system can be used to determine the origin of intestinal T EM cells, including Th17 cells. It is important to note that in the systemic homeostatic proliferation under lymphopenic conditions, cell populations can be divided into two groups by their division rate-slow, in which cells divide only once or twice per week, and fast, in which cells divide more than seven times within 7 d (46,47). Slow proliferation depends on IL-7, occurs in secondary lymphoid organs, and produces a cell population that retains the CD44 low CD62L high naive phenotype and has limited differentiation potential (2).…”

“…Slow proliferation depends on IL-7, occurs in secondary lymphoid organs, and produces a cell population that retains the CD44 low CD62L high naive phenotype and has limited differentiation potential (2). In contrast, fast proliferation produces cells that robustly differentiate into the CD44 high CD62L low T EM -phenotype cells (46,47). However, it is unclear whether the two distinct types of homeostatic proliferations may also occur in an organ-specific fashion such as in the intestine and MLNs.…”