NKT cells inhibit antigen-specific effector CD8 T cell induction to skin viral proteins

Mattarollo, Stephen R., Yong, Michelle, Gosmann, Christina, Choyce, Allison, Chan, Dora, Leggatt, Graham R. and Frazer, Ian H. (2011) NKT cells inhibit antigen-specific effector CD8 T cell induction to skin viral proteins. Journal of Immunology, 187 4: 1601-1608. doi:10.4049/jimmunol.1100756

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Author Mattarollo, Stephen R.
Yong, Michelle
Gosmann, Christina
Choyce, Allison
Chan, Dora
Leggatt, Graham R.
Frazer, Ian H.
Title NKT cells inhibit antigen-specific effector CD8 T cell induction to skin viral proteins
Journal name Journal of Immunology   Check publisher's open access policy
ISSN 0022-1767
Publication date 2011-08-01
Sub-type Article (original research)
DOI 10.4049/jimmunol.1100756
Open Access Status File (Author Post-print)
Volume 187
Issue 4
Start page 1601
End page 1608
Total pages 8
Place of publication Bethesda, MD, United States
Publisher American Association of Immunologists
Language eng
Abstract Type 1 diabetes (T1D) results from autoimmune destruction of insulin-producing pancreatic β cells. Therapies need to incorporate strategies to overcome the genetic defects that impair induction or maintenance of peripheral T-cell tolerance and contribute to disease development. We tested whether the enforced expression of an islet autoantigen in antigen-presenting cells (APC) counteracted peripheral T-cell tolerance defects in autoimmune-prone NOD mice. We observed that insulin-specific CD8(+) T cells transferred to mice in which proinsulin was transgenically expressed in APCs underwent several rounds of division and the majority were deleted. Residual insulin-specific CD8(+) T cells were rendered unresponsive and this was associated with TCR downregulation, loss of tetramer binding and expression of a range of co-inhibitory molecules. Notably, accumulation and effector differentiation of insulin-specific CD8(+) T cells in pancreatic lymph nodes was prominent in non-transgenic recipients but blocked by transgenic proinsulin expression. This shift from T-cell priming to T-cell tolerance exemplifies the tolerogenic capacity of autoantigen expression by APC and the capacity to overcome genetic tolerance defects.
Formatted abstract
We recently demonstrated that CD1d-restricted NKT cells resident in skin can inhibit CD8 T cell-mediated graft rejection of human papillomavirus E7-expressing skin through an IFN-γ–dependent mechanism. In this study, we examined the role of systemically derived NKT cells in regulating the rejection of skin grafts expressing viral proteins. In lymph nodes draining transplanted skin, Ag-specific CD8 T cell proliferation, cytokine production, and cytotoxic activity were impaired by NKT cells. NKT cell suppression was mediated via CD11c+ dendritic cells. Inhibition of CD8 T cell function did not require Foxp3+ regulatory T cells or NKT cell-secreted IFN-γ, IL-0, or IL-17. Thus, following skin grafting or immunization with human papillomavirus-E7 oncoprotein, NKT cells reduce the capacity of draining lymph node-resident APCs to cross-present Ag to CD8 T cell precursors, as evidenced by impaired expansion and differentiation to Ag-specific CD8 T effector cells. Therefore, in the context of viral Ag challenge in the skin, systemic NKT cells limit the capacity for effective priming of adaptive immunity. 
Keyword Dendritic cells
Tumor immunosurveillance
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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UQ Diamantina Institute - Open Access Collection
UQ Diamantina Institute Publications
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Citation counts: TR Web of Science Citation Count  Cited 19 times in Thomson Reuters Web of Science Article | Citations
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