Defining a human T cell innateness gradient — ASN Events
  1. Schedule
  2. Session 6: Insights into the biology of innate T cells from imaging and transcriptomics
  3. Defining a human T cell innateness gradient

Defining a human T cell innateness gradient (#45)

Maria Gutierrez-Arcelus 1 2 3 , Alex R. Mola 1 , Susan K. Hannes 1 2 , Nikola C. Teslovich 4 , Watts F.M. Watts 1 , Michael B. Brenner 1 , Soumya Raychaudhuri 1 2 3 5 , Patrick J. Brennan 1
  1. Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
  2. Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
  3. Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
  4. Stanford University School of Medicine, Stanford, CA, USA
  5. Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK

The cell types that are the focus of our field, iNKT cells, MAIT cells, and γδ T cells, blur the line between innate and adaptive immunity, manifesting innate-like rapid responses in diverse inflammatory contexts, while also using adaptive-like antigen receptors generated in the thymus through somatic recombination to recognize defined antigens.  Understanding these cells that do not fit neatly into pre-existing notions of innate and adaptive immunity remains an interesting puzzle with only some pieces in place, and a fundamental question in our field.

To define the nature of human innate T cells, we undertook immunophenotyping and ultra-low-input, high-depth RNA-Seq analysis of iNKT cells, MAIT cells, Vδ1, Vδ2, Vδ3, and δ/αβ T cells, as well as adaptive and innate comparator cell populations, with the goal of identifying the transcriptional basis of T cell ‘innateness.’  To assess the global transcriptional relationships between cell types, we performed a series of bioinformatic analyses including comparative gene expression analysis using linear mixed models, principal component analysis, gene set enrichment analysis, and promoter/enhancer regulator prediction.  Findings were confirmed with extensive validation and functional perturbation of key pathways.

Our quantitative assessment of global transcriptional relationships revealed an innateness gradient in which innate T cells clustered distinctly between prototypical innate and adaptive populations.  Identification of the gene signatures that positively and negatively associated with this gradient allowed us to define a transcriptional basis for lymphocyte innateness, including PLZF-associated and PLZF-independent dimensions.  Key pathways operating in innate T cells included cytotoxicity, chemokine and cytokine networks, redox regulation, unique mechanisms of priming, and a myc-associated altered translational state defined by regulated ribosomal biogenesis.  Together, these studies demonstrate that innate T cells are a distinct arm of the immune system defined by the steady-state expression of shared transcriptional programming uncovered by studying these populations collectively.