CD4 and CD8 co-receptors modulate functional avidity of CD1b-restricted T cells

Charlotte A. James, Yuexin Xu, Melissa S. Aguilar, Lichen Jing, Erik D. Layton, Martine Gilleron, Adriaan J. Minnaard, Thomas J. Scriba, Cheryl L. Day, Edus H. Warren, David M. Koelle and Chetan Seshadri ()
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Charlotte A. James: University of Washington
Yuexin Xu: Clinical Research Division, Fred Hutchinson Cancer Research Center
Melissa S. Aguilar: University of Washington
Lichen Jing: University of Washington
Erik D. Layton: University of Washington
Martine Gilleron: Université de Toulouse, CNRS, UPS
Adriaan J. Minnaard: University of Groningen
Thomas J. Scriba: University of Cape Town
Cheryl L. Day: Emory University
Edus H. Warren: University of Washington
David M. Koelle: Clinical Research Division, Fred Hutchinson Cancer Research Center
Chetan Seshadri: University of Washington

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract T cells recognize mycobacterial glycolipid (mycolipid) antigens presented by CD1b molecules, but the role of CD4 and CD8 co-receptors in mycolipid recognition is unknown. Here we show CD1b-mycolipid tetramers reveal a hierarchy in which circulating T cells expressing CD4 or CD8 co-receptor stain with a higher tetramer mean fluorescence intensity than CD4-CD8- T cells. CD4+ primary T cells transduced with mycolipid-specific T cell receptors bind CD1b-mycolipid tetramer with a higher fluorescence intensity than CD8+ primary T cells. The presence of either CD4 or CD8 also decreases the threshold for interferon-γ secretion. Co-receptor expression increases surface expression of CD3ε, suggesting a mechanism for increased tetramer binding and activation. Targeted transcriptional profiling of mycolipid-specific T cells from individuals with active tuberculosis reveals canonical markers associated with cytotoxicity among CD8+ compared to CD4+ T cells. Thus, expression of co-receptors modulates T cell receptor avidity for mycobacterial lipids, leading to in vivo functional diversity during tuberculosis disease.

Date: 2022
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DOI: 10.1038/s41467-021-27764-w

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