The human T-cell repertoire grows up
- 1Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA
- 2Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA, USA
- 3Harvard Medical School; Boston, MA, USA
- 4Center for Immunology and Department of Microbiology and Immunology, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, USA
Correspondence: Marc K Jenkins, E-mail: email@example.com
To recognize major histocompatibility complex (MHC)-bound peptides from virtually any intracellular antigen, the adaptive immune system develops a vast pre-immune repertoire of T-cell clones, each with one of a seemingly infinite number of unique T-cell antigen receptors (TCRs). Studies in inbred mice have revealed several features of this repertoire.1, 2, 3, 4 First, the number of naive T cells that recognize a given MHC-bound foreign peptide is small, on the order of 1 cell per million, and consistent among genetically identical individuals. Second, the number of naive T cells that recognize one MHC-bound foreign peptide is likely to differ from the number that recognize another. And third, the number of naive T cells that recognize an MHC-bound foreign peptide correlates with the number of effector and memory cells produced during a primary immune response. Although some studies have been done in humans,5, 6 it is not yet clear whether the repertoire will be more complicated in humans due to MHC polymorphisms and extensive pathogen exposure.
In this issue of ICB, Neller et al.7 study the evolution of peptide:MHCI epitope-specific CD8+ T-cell populations in humans using cross-sectional evaluations of naive T-cell populations in umbilical cord blood and memory T-cell populations in adult blood. Using peptide:MHC multimer-based cell enrichment techniques, they enumerate CD8+ T cells specific for viral peptide:MHCI epitopes at birth, and show that these cells increase dramatically following antigen exposure in adulthood. By performing TCR-sequencing analysis, they observe a concomitant decrease in the TCR clonal diversity of T cells within these populations.
The use of umbilical cord blood samples provided an effective means of characterizing the initial frequency and clonal diversity of epitope-specific naive T-cell populations as they emerge from the human thymus and likely before any exposure to foreign antigens. This is not a trivial concern, as many foreign epitope-specific T cells in people who have never been exposed to that epitope have a memory cell phenotype5 perhaps due to homeostatic proliferation8 or cross-reactivity to similar peptides from environmental antigens.2, 9 Moreover, extrathymic proliferation is thought to have a major role in the maintenance of the naive T-cell pool in humans.10 By examining six different peptide:MHCI-specific CD8+ T-cell populations in human leukocyte antigen matched subjects, the authors found that like in mice, the number of naive T cells differed for different peptide:MHC ligands, and these frequencies were consistent across several individuals. This result suggests that MHC-driven selection is the main determinant of epitope-specific naive T-cell numbers in mouse secondary lymphoid organs and human cord blood.
Surprisingly, the hierarchy of T-cell frequencies for different viral epitopes was lost in peripheral blood samples from virus-seropositive subjects, indicating that clonal expansion was not proportional to the number of naive T cells in cord blood. Thus, variables other than naive T-cell frequency may determine the magnitude of the primary response, at least for certain peptides.11 It is also possible, however, that the naive T-cell frequencies for different viral epitopes changed between the time of birth and the time of viral infection. Indeed, the authors found that naive T-cell frequencies for two different viral epitopes in unexposed adults aligned with those in exposed adult blood rather than those in cord blood. Although it is not possible to reach a definitive conclusion with this limited sample, the results suggest the intriguing possibility that the naive T-cell frequency for a given foreign peptide:MHC epitope can change after birth by a process that does not involve direct recognition of that epitope. It is possible that certain clones in the population undergo homeostatic proliferation in response to interleukin-7 and a self peptide:MHC ligand, or in response to an MHC-bound foreign peptide with a related amino-acid sequence from an environmental antigen (Figure 1). The authors also reveal a winnowing of the TCR repertoire within all of the viral epitope-specific populations after infection, with a surprising loss of some public T-cell clones in some populations. This supports the presence of a competitive environment causing the selective loss of certain clonotypes, which is expected during the course of an immune response. However, it remains to be seen whether such selective processes are in effect during the period between birth and adulthood before the onset of the cognate immune response.
Model for repertoire change before exposure to foreign antigen. The figure depicts a cord blood repertoire of three T-cell clones each with a different TCR specific for slightly different conformations of the same MHC-bound peptide from virus X. All three clones have the naive cell surface phenotype. Sometime during adulthood, the host is exposed to a virus that has a peptide that is structurally homologous to the virus X peptide conformation recognized by clone 1 or a Virus X-like self peptide and IL-7, which causes clone 1 to proliferate and adopt the memory cell surface phenotype. Later in life the host is infected with virus X and all three clones proliferate and form memory cells. Note that clone 1 is overrepresented in the resulting memory cell pool compared with its frequency in cord blood.
Collectively, this study highlights the power of analyzing cord blood samples to define a true baseline repertoire of epitope-specific T cells in humans. In doing so, it raises interesting new questions about how epitope-specific naive T-cell populations evolve during the long lifespans of humans.
- Moon JJ, Chu HH, Pepper M, McSorley SJ, Jameson SC, Kedl RM et al. Naive CD4(+) T cell frequency varies for different epitopes and predicts repertoire diversity and response magnitude. Immunity 2007; 27: 203–213. | Article | PubMed | ISI | CAS |
- Nelson RW, Beisang D, Tubo NJ, Dileepan T, Wiesner DL, Nielsen K et al. T cell receptor cross-reactivity between similar foreign and self peptides influences naive cell population size and autoimmunity. Immunity 2015; 42: 95–107. | Article | PubMed | ISI |
- Haluszczak C, Akue AD, Hamilton SE, Johnson LD, Pujanauski L, Teodorovic Let al. The antigen-specific CD8+ T cell repertoire in unimmunized mice includes memory phenotype cells bearing markers of homeostatic expansion.J Exp Med 2009; 206: 435–448. | Article | PubMed | ISI | CAS |
- Obar JJ, Khanna KM, Lefrancois L. Endogenous naive CD8+ T cell precursor frequency regulates primary and memory responses to infection. Immunity2008; 28: 859–869. | Article | PubMed | CAS |
- Su LF, Kidd BA, Han A, Kotzin JJ, Davis MM. Virus-specific CD4(+) memory-phenotype T cells are abundant in unexposed adults. Immunity 2013; 38: 373–383. | Article | PubMed | ISI | CAS |
- Campion SL, Brodie TM, Fischer W, Korber BT, Rossetti A, Goonetilleke N et al. Proteome-wide analysis of HIV-specific naive and memory CD4(+) T cells in unexposed blood donors. J Exp Med 2014; 211: 1273–1280. | Article | PubMed | ISI |
- Neller MA, Ladell K, McLaren JE, Matthews KK, Gostick E, Pentier JM et al. Naïve CD8+ T-cell precursors display structured TCR repertoires and composite antigen-driven selection dynamics. Immunol Cell Biol (e-pub ahead of print 24 March 2015; doi:10.1038/icb.2015.17). | Article |
- Surh CD, Sprent J. Homeostasis of naive and memory T cells. Immunity2008; 29: 848–862. | Article | PubMed | ISI | CAS |
- Birnbaum ME, Mendoza JL, Sethi DK, Dong S, Glanville J, Dobbins J et al. Deconstructing the peptide-MHC specificity of T cell recognition. Cell 2014;157: 1073–1087. | Article | PubMed | ISI | CAS |
- den Braber I, Mugwagwa T, Vrisekoop N, Westera L, Mögling R, de Boer AB et al. Maintenance of peripheral naive T cells is sustained by thymus output in mice but not humans. Immunity 2012; 36: 288–297. | Article | PubMed | ISI | CAS |
- La Gruta NL, Rothwell WT, Cukalac T, Swan NG, Valkenburg SA, Kedzierska Ket al. Primary CTL response magnitude in mice is determined by the extent of naive T cell recruitment and subsequent clonal expansion. J Clin Invest 2010;120: 1885–1894. | Article | PubMed | ISI | CAS |