Tolerance is established in polyclonal CD4 + T cells by distinct mechanisms, according to self-peptide expression patterns

Deepali Malhotra; Jonathan L. Linehan; Thamotharampillai Dileepan; You Jeong Lee; Whitney E. Purtha; Jennifer V. Lu; Ryan W. Nelson; Brian T. Fife; Harry T. Orr; Mark S. Anderson; Kristin A. Hogquist; Marc K. Jenkins

doi:10.1038/ni.3327

Tolerance is established in polyclonal CD4 + T cells by distinct mechanisms, according to self-peptide expression patterns

Deepali Malhotra, Jonathan L. Linehan, Thamotharampillai Dileepan, You Jeong Lee, Whitney E. Purtha, Jennifer V. Lu, Ryan W. Nelson, Brian T. Fife, Harry T. Orr, Mark S. Anderson, Kristin A. Hogquist, Marc K. Jenkins

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Abstract

Studies of repertoires of mouse monoclonal CD4 + T cells have revealed several mechanisms of self-tolerance; however, which mechanisms operate in normal repertoires is unclear. Here we studied polyclonal CD4 + T cells specific for green fluorescent protein expressed in various organs, which allowed us to determine the effects of specific expression patterns on the same epitope-specific T cells. Peptides presented uniformly by thymic antigen-presenting cells were tolerated by clonal deletion, whereas peptides excluded from the thymus were ignored. Peptides with limited thymic expression induced partial clonal deletion and impaired effector T cell potential but enhanced regulatory T cell potential. These mechanisms were also active for T cell populations specific for endogenously expressed self antigens. Thus, the immunotolerance of polyclonal CD4 + T cells was maintained by distinct mechanisms, according to self-peptide expression patterns.

Original language	English (US)
Pages (from-to)	187-195
Number of pages	9
Journal	Nature immunology
Volume	17
Issue number	2
DOIs	https://doi.org/10.1038/ni.3327
State	Published - Feb 1 2016

Bibliographical note

Funding Information:
We thank D. Mueller for reviewing the manuscript; J. Walter and O. Rainwater for technical assistance; P. Lauer (and Aduro Biotech) for the Lm-eGFP strain PL1113. Supported by the US National Institutes of Health (P01 AI35296 to M.K.J. and K.A.H.; F32 AI114050 to D.M.; T32 GM008244 and F30 DK093242 to R.W.N.; T32 AI07313 to J.L.L.; K99 AI114884 to Y.J.L.), the Wallin Neuroscience Discovery Fund (to H.T.O. and M.K.J.) and the Juvenile Diabetes Research Foundation (2-2011-662 to B.T.F.).

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http://europepmc.org/articles/pmc4718891

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Malhotra, D., Linehan, J. L., Dileepan, T., Lee, Y. J., Purtha, W. E., Lu, J. V., Nelson, R. W., Fife, B. T., Orr, H. T., Anderson, M. S., Hogquist, K. A., & Jenkins, M. K. (2016). Tolerance is established in polyclonal CD4 + T cells by distinct mechanisms, according to self-peptide expression patterns. Nature immunology, 17(2), 187-195. https://doi.org/10.1038/ni.3327

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title = "Tolerance is established in polyclonal CD4 + T cells by distinct mechanisms, according to self-peptide expression patterns",

abstract = "Studies of repertoires of mouse monoclonal CD4 + T cells have revealed several mechanisms of self-tolerance; however, which mechanisms operate in normal repertoires is unclear. Here we studied polyclonal CD4 + T cells specific for green fluorescent protein expressed in various organs, which allowed us to determine the effects of specific expression patterns on the same epitope-specific T cells. Peptides presented uniformly by thymic antigen-presenting cells were tolerated by clonal deletion, whereas peptides excluded from the thymus were ignored. Peptides with limited thymic expression induced partial clonal deletion and impaired effector T cell potential but enhanced regulatory T cell potential. These mechanisms were also active for T cell populations specific for endogenously expressed self antigens. Thus, the immunotolerance of polyclonal CD4 + T cells was maintained by distinct mechanisms, according to self-peptide expression patterns.",

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note = "Funding Information: We thank D. Mueller for reviewing the manuscript; J. Walter and O. Rainwater for technical assistance; P. Lauer (and Aduro Biotech) for the Lm-eGFP strain PL1113. Supported by the US National Institutes of Health (P01 AI35296 to M.K.J. and K.A.H.; F32 AI114050 to D.M.; T32 GM008244 and F30 DK093242 to R.W.N.; T32 AI07313 to J.L.L.; K99 AI114884 to Y.J.L.), the Wallin Neuroscience Discovery Fund (to H.T.O. and M.K.J.) and the Juvenile Diabetes Research Foundation (2-2011-662 to B.T.F.).",

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AU - Hogquist, Kristin A.

AU - Jenkins, Marc K.

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Tolerance is established in polyclonal CD4 + T cells by distinct mechanisms, according to self-peptide expression patterns

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