Expression of Intestine-Specific Antigen Reveals Novel Pathways of CD8 T Cell Tolerance Induction

Abstract Administration of a single dose of anti-CD40L mAb at the time of allogeneic BM transplantation tolerizes peripheral alloreactive T cells and permits establishment of mixed hematopoietic chimerism in mice. Once engrafted, mixed chimeras are systemically tolerant to donor Ags through a central deletion mechanism and will accept any donor organ indefinitely. We previously found that the PD-1/PD-L1 pathway is required for CD8 T-cell tolerance in this model. However, the cell population that must express PD-1 and the role of other inhibitory molecules were unknown. Here, we report that LAG-3 is required for long-term peripheral CD8 but not CD4 T-cell tolerance and that this requirement is CD8 cell-extrinsic. In contrast, adoptive transfer studies revealed a CD8 T cell–intrinsic requirement for CTLA4/B7.1/B7.2 and for PD-1 for CD8 T-cell tolerance induction. We also observed that both PD-L1 and PD-L2 are independently required on donor cells to achieve T-cell tolerance. Finally, we uncovered a requirement for TGF-β signaling into T cells to achieve peripheral CD8 but not CD4 T-cell tolerance in this in vivo system.

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Irradiation and IL-15 promote loss of CD8 T-cell tolerance in response to lymphopenia

Blood ◽

10.1182/blood-2009-06-227298 ◽

2010 ◽

Vol 115 (11) ◽

pp. 2196-2202 ◽

Cited By ~ 9

Author(s):

Thilo Oelert ◽

Maria Papatriantafyllou ◽

Georg Pougialis ◽

Günter J. Hämmerling ◽

Bernd Arnold ◽

...

Keyword(s):

T Cell ◽

T Lymphocytes ◽

Tolerance Induction ◽

Cd8 T Cell ◽

Adoptive T Cell Therapy ◽

Cancer Therapies ◽

T Cell Tolerance ◽

Cell Tolerance ◽

T Cell Therapy ◽

Effector Functions

Abstract Functional inactivation of self-reactive T lymphocytes contributes to the maintenance of immunologic self-tolerance. At the same time, tolerance induction limits immune responses against tumors expressing tolerizing self-antigens. Some cancer therapies include the adoptive transfer of tumor-reactive T lymphocytes into lymphopenic patients. Lymphopenia provides an activation signal to T lymphocytes, which undergo lymphopenia-induced proliferation (LIP), acquire effector functions, and reject tumors. However, it is so far unknown to which extent LIP may result in reversal of established antigen-specific CD8 T-cell tolerance. Here, we report that neonatally induced dominant CD8 T-cell tolerance remained stable under lymphopenic conditions also in the presence of systemic inflammation induced by Toll-like receptor ligands. However, when lymphopenic recipients were irradiated, the tolerant status was lost, because CD8 T cells acquired effector functions in an interleukin-15–dependent fashion and efficiently rejected tumors. In conclusion, we show that lymphopenia is not sufficient to break CD8 T-cell tolerance. Furthermore, we demonstrate that pretreatment regimens are crucial to circumvent this problem and to optimize adoptive T-cell therapy.

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