Adaptive Tolerance of CD4+ T Cells In Vivo: Multiple Thresholds in Response to a Constant Level of Antigen Presentation

Abstract

The in vivo T cell response to persistent Ag contains a hyporesponsive phase following an initial expansion and subsequent partial deletion of the responding cells. The mechanism(s) responsible for this tolerance process is poorly understood. In this study, we describe a new paired transgenic model (TCR and Ag), which within 7–14 days produces 20–40 million hyporesponsive T cells. This state is characterized by an 85–95% reduction in all cytokine production, an impairment of re-expression of CD25 and CD69, and a desensitization of the proliferative response to Ag. TCR levels were normal, and in vivo mixing experiments showed no evidence for active suppression. The hyporesponsiveness partially dissipated without proliferation when the cells were transferred into a non-Ag-bearing host. If the second host expressed Ag, the T cells initially regained responsiveness, but then slowly entered an even deeper state of tolerance characterized by an additional 7- to 10-fold lowering of cytokine production and a greater desensitization of proliferation. Surprisingly, this readaptation took place with the same level of Ag presentation, suggesting that other parameters can influence the tolerance threshold. Both the readjustment in sensitivity and the reversal without Ag convincingly demonstrate for the first time a truly adaptive tolerance process in CD4+ T cells in vivo.

Reviving Function in CD4+ T Cells Adapted to Persistent Systemic Antigen

“…S2). Thus, T cells that had expanded under persistent antigenic stimulation in lymphopenic hosts appeared to have developed a state of functional unresponsiveness similar to that previously described as T cell adaptation (3,4). Whereas unresponsive T cells did not produce IL-2, they secreted IFN-␥ in response to anti-CD3 stimulation (see supplemental Fig.…”

“…In fact, it has been shown that adapted T cells are characterized by their ability to calibrate their responsiveness to a persistent Ag (2)(3)(4). In this study, we show for the first time that negative costimulation was critical for CD4 ϩ T cells to maintain their adaptation to systemic mHA and that negative costimulation blockade by Ab treatment converted adapted T cells into aggressive effector cells.…”

“…M inor histocompatibility Ags (mHA) 3 are thought to be key molecules in the graft-versus-tumor effect after bone marrow stem cell transplantation (1). Recipient's mHA are considered to be the molecular targets recognized by donor T cells contained within the graft that promote this effect.…”

“…How this situation might impair the capacity of T cells to promote antileukemia immunity is unknown. T cells that are chronically stimulated by their cognate Ag are known to develop the capacity to tailor, or adapt, their activation threshold to the strength of ambient Ag presentation (2)(3)(4). Because of apparent functional dysfunction such as lack of IL-2 secretion and poor proliferation upon subsequent antigenic challenge, T cell adaptation has very often been confused with T cell anergy.…”

“…There are, however, major functional differences between anergized T cells and T cells adapted to persistent Ag. Contrary to anergized T cells, which can be induced by a single administration of a high dose of soluble peptide Ag or chemically modified Ag-pulsed APC, adapted CD4 ϩ T cells require in vivo Ag persistence to maintain their unresponsive state and adaptation to Ag is reversible upon T cell removal from the Ag-bearing host (3). Second, adaptation cannot be reversed by IL-2 because adapted T cells do not express high-affinity IL-2R (3).…”