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Insights into immune system development and function from mouse T-cell repertoires

  1. Aleksandra M. Walczakb
  1. aJoseph Henry Laboratories, Princeton University, Princeton, NJ 08544;
  2. bLaboratoire de Physique Théorique, UMR8549, CNRS, École Normale Supérieure, 75005 Paris, France;
  3. cCancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 08903;
  4. dInstitute for Advanced Study, Princeton NJ 08540;
  5. eLaboratoire de Physique Statistique, UMR8550, CNRS, École Normale Supérieure, 75005 Paris, France

  1. Contributed by Curtis G. Callan Jr., January 5, 2017 (sent for review November 9, 2016; reviewed by Benjamin Chain and Arup K. Chakraborty)

Significance

The immune system defends against pathogens in part via a diverse population of T cells that display different surface receptor proteins [T-cell receptors (TCRs)] designed to recognize MHC-presented foreign peptides. Receptor diversity is produced by an initial random gene recombination process, followed by selection for proteins that fold correctly and bind weakly to self-peptides. Using data from mice of different ages, from embryo to young adult, we quantify the changes with time in the way receptors are generated and selected for function. We find a strong increase in repertoire diversity, occurring shortly after birth, due to a sharp increase in the number of random nucleotide insertions in the primitive TCR gene recombination process. Differences between thymic and blood TCR sequence distributions allow us to infer subtle details of this “turning on” of the mouse immune system.

Abstract

The ability of the adaptive immune system to respond to arbitrary pathogens stems from the broad diversity of immune cell surface receptors. This diversity originates in a stochastic DNA editing process (VDJ recombination) that acts on the surface receptor gene each time a new immune cell is created from a stem cell. By analyzing T-cell receptor (TCR) sequence repertoires taken from the blood and thymus of mice of different ages, we quantify the changes in the VDJ recombination process that occur from embryo to young adult. We find a rapid increase with age in the number of random insertions and a dramatic increase in diversity. Because the blood accumulates thymic output over time, blood repertoires are mixtures of different statistical recombination processes, and we unravel the mixture statistics to obtain a picture of the time evolution of the early immune system. Sequence repertoire analysis also allows us to detect the statistical impact of selection on the output of the VDJ recombination process. The effects we find are nearly identical between thymus and blood, suggesting that our analysis mainly detects selection for proper folding of the TCR receptor protein. We further find that selection is weaker in laboratory mice than in humans and it does not affect the diversity of the repertoire.

Footnotes

  • ↵1Z.S. and Y.E. contributed equally to this work.

  • ↵2To whom correspondence should be addressed. Email: ccallan{at}princeton.edu.

  • Author contributions: Z.S., Y.E., C.G.C., A.J.L., T.M., and A.M.W. designed research; Z.S., Y.E., C.S.D., C.G.C., T.M., and A.M.W. performed research; Z.S., Y.E., C.G.C., T.M., and A.M.W. analyzed data; and Z.S., Y.E., C.G.C., A.J.L., T.M., and A.M.W. wrote the paper.

  • Reviewers: B.C., University College London; and A.K.C., Massachusetts Institute of Technology.

  • The authors declare no conflict of interest.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1700241114/-/DCSupplemental.

Freely available online through the PNAS open access option.

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