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Ly49 C/I-dependent NKT cell-derived IL-10 is required for corneal graft survival and peripheral tolerance
C M Watte1, T Nakamura, C H Lau
1Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, 20 Staniford Street, Boston, MA 02114, USA.
Insights
The Ly49 C/I inhibitory receptor is crucial for NKT cells to induce peripheral tolerance. Blocking this receptor prevents IL-10 production, hindering tolerance development and corneal graft survival.
Area of Science:
- Immunology
- Cellular Biology
- Transplantation Immunology
Background:
- Ly49 molecules significantly influence Natural Killer (NK) and Natural Killer T (NKT) cell responses.
- The Ly49 C/I receptor is an inhibitory receptor that down-modulates cellular proliferation, Interferon-gamma (IFN-γ) production, and cytotoxic activity.
- Invariant NKT cells expressing Ly49 C/I are essential for peripheral tolerance induced through ocular exposure.
Purpose of the Study:
- To investigate the functional role of the NK inhibitory receptor Ly49 C/I in the development of peripheral tolerance.
- To determine if blocking Ly49 C/I impacts antigen-specific suppression and immune responses.
- To assess the effect of Ly49 C/I blockade on NKT cell cytokine production and corneal allograft survival.
Main Methods:
- Utilized a model of peripheral tolerance induced via the eye.
- Employed blocking antibodies, both in vivo and in vitro, to interfere with Ly49 C/I receptor ligation.
- Analyzed NKT cell production of Interleukin-10 (IL-10) and IFN-γ.
- Assessed corneal graft survival rates.
- Examined Ly49 C/I cross-linking on CD4(+) NKT cells under T-cell receptor (TCR) stimulation.
Main Results:
- Blocking Ly49 C/I ligation prevented NKT cell production of IL-10, which is critical for tolerance development.
- Interference with Ly49 C/I function abrogated the development of antigen-specific suppression.
- Ly49 C/I-blocking antibodies significantly reduced corneal graft survival, indicating a failure of eye-induced tolerance.
- Cross-linking Ly49 C/I on CD4(+) NKT cells, in conjunction with TCR stimulation, increased IL-10 mRNA and decreased IFN-γ production.
Conclusions:
- The Ly49 C/I inhibitory receptor plays a vital role in the development of peripheral tolerance to foreign antigens.
- Ly49 C/I regulates NKT cell-mediated immune responses, including IL-10 production, essential for establishing tolerance.
- This study expands the understanding of Ly49 inhibitory receptors from regulating self-reactivity to influencing tolerance to foreign antigens in a broader context.
Abstract:
Similar to their activity on NK cells, Ly49 molecules play a pivotal role in influencing how NKT cells respond. It is known that Ly49 C/I is an inhibitory receptor capable of down-modulating proliferation, IFN-gamma response, and cytotoxic activity in cells that express it. In a model of peripheral tolerance induced via the eye, we observed that Ly49 C/I-positive, invariant NKT cells were required. To test if the NK inhibitory receptor functionally contributed to tolerance development, we used blocking antibody, in vivo and in vitro, to interfere with the development of antigen-specific suppression. A result of blocking ligation of Ly49 C/I inhibitory receptor prevented NKT cell production of IL-10 and the subsequent development of tolerance. Ly49 C/I-blocking antibodies also prevented corneal graft survival, a phenomenon dependent on eye-induced tolerance. Furthermore, in the presence of TCR stimulation, cross-linking of Ly49 C/I on CD4(+) NKT cells stimulated an increase in IL-10 mRNA and a decrease in IFN-gamma. The concept of Ly49 inhibitory receptors regulating immune reactivity to self by regulating immune activity of individual cells is thus expanded to include a role for the inhibitory receptors in the more global process of peripheral tolerance to foreign antigens.
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