A TCR mechanotransduction signaling loop induces negative selection in the thymus

Jinsung Hong; Chenghao Ge; Prithiviraj Jothikumar; Zhou Yuan; Baoyu Liu; Ke Bai; Kaitao Li; William Rittase; Miho Shinzawa; Yun Zhang; Amy Palin; Paul Love; Xinhua Yu; Khalid Salaita; Brian D Evavold; Alfred Singer; Cheng Zhu

doi:10.1038/s41590-018-0259-z

A TCR mechanotransduction signaling loop induces negative selection in the thymus

Nat Immunol. 2018 Dec;19(12):1379-1390. doi: 10.1038/s41590-018-0259-z. Epub 2018 Nov 12.

Authors

Jinsung Hong^{1

2

3}, Chenghao Ge^{2

4}, Prithiviraj Jothikumar^{2

4}, Zhou Yuan^{2

4}, Baoyu Liu^{2

4

5}, Ke Bai^{2

4

6}, Kaitao Li^{2

4}, William Rittase^{1

2}, Miho Shinzawa⁷, Yun Zhang⁸, Amy Palin^{9

10}, Paul Love⁹, Xinhua Yu¹¹, Khalid Salaita⁸, Brian D Evavold^{12

5}, Alfred Singer⁷, Cheng Zhu^{13

14

15}

Affiliations

¹ Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA.
² Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA.
³ Vaccine Production Program Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institute of Health, Gaithersburg, MD, USA.
⁴ Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA.
⁵ Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA.
⁶ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institute of Health, Bethesda, MD, USA.
⁷ Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁸ Department of Chemistry, Emory University, Atlanta, GA, USA.
⁹ Section on Hematopoiesis and Lymphocyte Biology, Eunice Kennedy Shriver National Institute of Child Health and Development, National Institutes of Health, Bethesda, MD, USA.
¹⁰ Experimental Immunology Branch, National Cancer Institute National Institutes of Health, Bethesda, MD, USA.
¹¹ Division of Epidemiology, Biostatistics and Environment Health, University of Memphis, Memphis, TN, USA.
¹² Department of Immunology and Microbiology, Emory University School of Medicine, Atlanta, GA, USA.
¹³ Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA. [email protected].
¹⁴ Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA. [email protected].
¹⁵ Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA. [email protected].

Abstract

The T cell antigen receptor (TCR) expressed on thymocytes interacts with self-peptide major histocompatibility complex (pMHC) ligands to signal apoptosis or survival. Here, we found that negative-selection ligands induced thymocytes to exert forces on the TCR and the co-receptor CD8 and formed cooperative TCR-pMHC-CD8 trimolecular 'catch bonds', whereas positive-selection ligands induced less sustained thymocyte forces on TCR and CD8 and formed shorter-lived, independent TCR-pMHC and pMHC-CD8 bimolecular 'slip bonds'. Catch bonds were not intrinsic to either the TCR-pMHC or the pMHC-CD8 arm of the trans (cross-junctional) heterodimer but resulted from coupling of the extracellular pMHC-CD8 interaction to the intracellular interaction of CD8 with TCR-CD3 via associated kinases to form a cis (lateral) heterodimer capable of inside-out signaling. We suggest that the coupled trans-cis heterodimeric interactions form a mechanotransduction loop that reinforces negative-selection signaling that is distinct from positive-selection signaling in the thymus.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Clonal Deletion / immunology
Mechanotransduction, Cellular / immunology*
Mice
Mice, Transgenic
Receptors, Antigen, T-Cell / immunology*
Receptors, Antigen, T-Cell / metabolism
Thymocytes / immunology*
Thymocytes / metabolism
Thymus Gland / immunology*

Substances

Receptors, Antigen, T-Cell

Abstract

Publication types

MeSH terms

Substances

Grants and funding