Homeostasis-Stimulated Proliferation Drives Naive T Cells to Differentiate Directly into Memory T Cells

Abstract

The developmental requirements for immunological memory, a central feature of adaptive immune responses, is largely obscure. We show that as naive CD8 T cells undergo homeostasis-driven proliferation in lymphopenic mice in the absence of overt antigenic stimulation, they progressively acquire phenotypic and functional characteristics of antigen-induced memory CD8 T cells. Thus, the homeostasis-induced memory CD8 T cells express typical memory cell markers, lyse target cells directly in vitro and in vivo, respond to lower doses of antigen than naive cells, and secrete interferon γ faster upon restimulation. Like antigen-induced memory T cell differentiation, the homeostasis-driven process requires T cell proliferation and, initially, the presence of appropriate restricting major histocompatibility complexes, but it differs by occurring without effector cell formation and without requiring interleukin 2 or costimulation via CD28. These findings define repetitive cell division plus T cell receptor ligation as the basic requirements for naive to memory T cell differentiation.

Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy

“…It has long been observed that transfer of small numbers of T cells into lymphopenic hosts results in T-cell expansion, a process described as homeostatic proliferation [9][10][11][12][13][14][15][16]. As the T cells proliferate, they assume an Ag-experienced or memory phenotype, which is indicated by upregulation of CD44, Ly6C and CD122 (IL-2-IL-15Rβ) [12,15].…”

“…As the T cells proliferate, they assume an Ag-experienced or memory phenotype, which is indicated by upregulation of CD44, Ly6C and CD122 (IL-2-IL-15Rβ) [12,15]. This T-cell expansion and acquisition of a memory phenotype is also associated with enhanced effector functions, determined by ex vivo analysis of interferon-γ (IFN-γ) release and cytolysis [12,14,15].…”

“…As the T cells proliferate, they assume an Ag-experienced or memory phenotype, which is indicated by upregulation of CD44, Ly6C and CD122 (IL-2-IL-15Rβ) [12,15]. This T-cell expansion and acquisition of a memory phenotype is also associated with enhanced effector functions, determined by ex vivo analysis of interferon-γ (IFN-γ) release and cytolysis [12,14,15]. In a recent autoimmunity study, King et al showed that the inherent lymphopenia in non-obese diabetic (NOD) mice and increased expression of IL-21 drives the homeostatic expansion of autoreactive cells, precipitating self-tissue destruction [17].…”

“…2C TCR transgenic T cells are specific for an L d -restricted α-ketoglutarate dehydrogenase epitope or the SIYRYYGL peptide in the context MHC I H2-K b . These cells expand homeostatically in Rag −/− mice and specifically treat tumors, at a comparable level to the T cells derived from Ag-specific vaccination [15]. Dummer et al observed that adoptive transfer of a polyclonal population of T cells into a Rag −/− or sublethally irradiated mouse specifically inhibits tumor growth [18].…”

“…The proliferation of adoptively transferred Tcells in lymphopenic hosts can be reduced in a dose-dependent manner, either by increasing the total number of Ag-specific cells transfused or by co-transferring an 'irrelevant' population of Tcells [9,15,16,22]. Host CD8 + Tcells have a dominant role in modulating both donor CD8 + and CD4 + T-cell expansion in lymphopenic hosts [16].…”