Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Transcriptional insights into the CD8+ T cell response to infection and memory T cell formation


After infection, many factors coordinate the population expansion and differentiation of CD8+ effector and memory T cells. Using data of unparalleled breadth from the Immunological Genome Project, we analyzed the CD8+ T cell transcriptome throughout infection to establish gene-expression signatures and identify putative transcriptional regulators. Notably, we found that the expression of key gene signatures can be used to predict the memory-precursor potential of CD8+ effector cells. Long-lived memory CD8+ cells ultimately expressed a small subset of genes shared by natural killer T and γδ T cells. Although distinct inflammatory milieu and T cell precursor frequencies influenced the differentiation of CD8+ effector and memory populations, core transcriptional signatures were regulated similarly, whether polyclonal or transgenic, and whether responding to bacterial or viral model pathogens. Our results provide insights into the transcriptional regulation that influence memory formation and CD8+ T cell immunity.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Gene-expression profiles associated with the activation and memory formation of CD8+ T cells.
Figure 2: Coregulated genes can be used to predict transcriptional regulation of T cell activation.
Figure 3: Regulation of core gene-expression modules by memory precursor cells.
Figure 4: Common gene-expression patterns of transgenic and endogenous CD8+ effector and memory T cells.
Figure 5: Regulation of genes associated with activation state is independent of infection.
Figure 6: Genes induced in CD8+ memory T cells correlate with gene expression by NKT cells and activated γδ T cells.

Accession codes

Primary accessions

Gene Expression Omnibus


  1. 1

    Heng, T.S. & Painter, M.W. The Immunological Genome Project: networks of gene expression in immune cells. Nat. Immunol. 9, 1091–1094 (2008).

    CAS  Google Scholar 

  2. 2

    Haining, W.N. et al. Identification of an evolutionarily conserved transcriptional signature of CD8 memory differentiation that is shared by T and B cells. J. Immunol. 181, 1859–1868 (2008).

    CAS  Article  Google Scholar 

  3. 3

    Kaech, S.M., Hemby, S., Kersh, E. & Ahmed, R. Molecular and functional profiling of memory CD8 T cell differentiation. Cell 111, 837–851 (2002).

    CAS  Article  Google Scholar 

  4. 4

    Sarkar, S. et al. Functional and genomic profiling of effector CD8 T cell subsets with distinct memory fates. J. Exp. Med. 205, 625–640 (2008).

    CAS  Article  Google Scholar 

  5. 5

    Wirth, T.C. et al. Repetitive antigen stimulation induces stepwise transcriptome diversification but preserves a core signature of memory CD8+ T cell differentiation. Immunity 33, 128–140 (2010).

    CAS  Article  Google Scholar 

  6. 6

    Kaech, S.M. & Ahmed, R. Memory CD8+ T cell differentiation: initial antigen encounter triggers a developmental program in naive cells. Nat. Immunol. 2, 415–422 (2001).

    CAS  Article  Google Scholar 

  7. 7

    Busch, D.H., Kerksiek, K.M. & Pamer, E.G. Differing roles of inflammation and antigen in T cell proliferation and memory generation. J. Immunol. 164, 4063–4070 (2000).

    CAS  Article  Google Scholar 

  8. 8

    Badovinac, V.P., Haring, J.S. & Harty, J.T. Initial T cell receptor transgenic cell precursor frequency dictates critical aspects of the CD8+ T cell response to infection. Immunity 26, 827–841 (2007).

    CAS  Article  Google Scholar 

  9. 9

    Haluszczak, C. et al. The antigen-specific CD8+ T cell repertoire in unimmunized mice includes memory phenotype cells bearing markers of homeostatic expansion. J. Exp. Med. 206, 435–448 (2009).

    CAS  Article  Google Scholar 

  10. 10

    Yamada, T., Park, C.S., Mamonkin, M. & Lacorazza, H.D. Transcription factor ELF4 controls the proliferation and homing of CD8+ T cells via the Kruppel-like factors KLF4 and KLF2. Nat. Immunol. 10, 618–626 (2009).

    CAS  Article  Google Scholar 

  11. 11

    Beuneu, H. et al. Visualizing the functional diversification of CD8+ T cell responses in lymph nodes. Immunity 33, 412–423 (2010).

    CAS  Article  Google Scholar 

  12. 12

    Grayson, J.M., Zajac, A.J., Altman, J.D. & Ahmed, R. Cutting edge: increased expression of Bcl-2 in antigen-specific memory CD8+ T cells. J. Immunol. 164, 3950–3954 (2000).

    CAS  Article  Google Scholar 

  13. 13

    Gründemann, C. et al. Cutting edge: identification of E-cadherin as a ligand for the murine killer cell lectin-like receptor G1. J. Immunol. 176, 1311–1315 (2006).

    Article  Google Scholar 

  14. 14

    Dietz, S.B., Whitaker-Menezes, D. & Lessin, S.R. The role of αEβ7 integrin (CD103) and E-cadherin in epidermotropism in cutaneous T-cell lymphoma. J. Cutan. Pathol. 23, 312–318 (1996).

    CAS  Article  Google Scholar 

  15. 15

    Pearce, E.L. et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460, 103–107 (2009).

    CAS  Article  Google Scholar 

  16. 16

    Araki, K. et al. mTOR regulates memory CD8 T-cell differentiation. Nature 460, 108–112 (2009).

    CAS  Article  Google Scholar 

  17. 17

    van der Windt, G.J. et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 36, 68–78 (2012).

    CAS  Article  Google Scholar 

  18. 18

    Gautier, E.L. et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat. Immunol. 13, 1118–1128 (2012).

    CAS  Article  Google Scholar 

  19. 19

    Joshi, N.S. et al. Inflammation directs memory precursor and short-lived effector CD8+ T cell fates via the graded expression of T-bet transcription factor. Immunity 27, 281–295 (2007).

    CAS  Article  Google Scholar 

  20. 20

    Rutishauser, R.L. et al. Transcriptional repressor Blimp-1 promotes CD8+ T cell terminal differentiation and represses the acquisition of central memory T cell properties. Immunity 31, 296–308 (2009).

    CAS  Article  Google Scholar 

  21. 21

    Kaech, S.M. et al. Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nat. Immunol. 4, 1191–1198 (2003).

    CAS  Article  Google Scholar 

  22. 22

    Schluns, K.S., Kieper, W.C., Jameson, S.C. & Lefrancois, L. Interleukin-7 mediates the homeostasis of naive and memory CD8 T cells in vivo. Nat. Immunol. 1, 426–432 (2000).

    CAS  Article  Google Scholar 

  23. 23

    Huster, K.M. et al. Selective expression of IL-7 receptor on memory T cells identifies early CD40L-dependent generation of distinct CD8+ memory T cell subsets. Proc. Natl. Acad. Sci. USA 101, 5610–5615 (2004).

    CAS  Article  Google Scholar 

  24. 24

    Yang, C.Y. et al. The transcriptional regulators Id2 and Id3 control the formation of distinct memory CD8+ T cell subsets. Nat. Immunol. 12, 1221–1229 (2011).

    CAS  Article  Google Scholar 

  25. 25

    Cannarile, M.A. et al. Transcriptional regulator Id2 mediates CD8+ T cell immunity. Nat. Immunol. 7, 1317–1325 (2006).

    CAS  Article  Google Scholar 

  26. 26

    D'Cruz, L.M., Lind, K.C., Wu, B.B., Fujimoto, J.K. & Goldrath, A.W. Loss of E protein transcription factors E2A and HEB delays memory-precursor formation during the CD8+ T-cell immune response. Eur. J. Immunol. 8, 2031–2041 (2012).

    Article  Google Scholar 

  27. 27

    Harty, J.T. & Badovinac, V.P. Shaping and reshaping CD8+ T-cell memory. Nat. Rev. Immunol. 8, 107–119 (2008).

    CAS  Article  Google Scholar 

  28. 28

    Obar, J.J., Khanna, K.M. & Lefrancois, L. Endogenous naive CD8+ T cell precursor frequency regulates primary and memory responses to infection. Immunity 28, 859–869 (2008).

    CAS  Article  Google Scholar 

  29. 29

    Obar, J.J. et al. Pathogen-induced inflammatory environment controls effector and memory CD8+ T cell differentiation. J. Immunol. 187, 4967–4978 (2011).

    CAS  Article  Google Scholar 

  30. 30

    Marzo, A.L. et al. Initial T cell frequency dictates memory CD8+ T cell lineage commitment. Nat. Immunol. 6, 793–799 (2005).

    CAS  Article  Google Scholar 

  31. 31

    Agarwal, P. et al. Gene regulation and chromatin remodeling by IL-12 and type I IFN in programming for CD8 T cell effector function and memory. J. Immunol. 183, 1695–1704 (2009).

    CAS  Article  Google Scholar 

  32. 32

    Sacerdote, P., Massi, P., Panerai, A.E. & Parolaro, D. In vivo and in vitro treatment with the synthetic cannabinoid CP55, 940 decreases the in vitro migration of macrophages in the rat: involvement of both CB1 and CB2 receptors. J. Neuroimmunol. 109, 155–163 (2000).

    CAS  Article  Google Scholar 

  33. 33

    Geserick, P., Kaiser, F., Klemm, U., Kaufmann, S.H. & Zerrahn, J. Modulation of T cell development and activation by novel members of the Schlafen (slfn) gene family harbouring an RNA helicase-like motif. Int. Immunol. 16, 1535–1548 (2004).

    CAS  Article  Google Scholar 

  34. 34

    Kallies, A. Distinct regulation of effector and memory T-cell differentiation. Immunol. Cell Biol. 86, 325–332 (2008).

    CAS  Article  Google Scholar 

  35. 35

    Sundrud, M.S. & Rao, A. Regulation of T helper 17 differentiation by orphan nuclear receptors: it's not just RORγt anymore. Immunity 28, 5–7 (2008).

    CAS  Article  Google Scholar 

Download references


We thank eBioscience, Affymetrix and Expression Analysis for support of the ImmGen Project. Supported by the US National Institutes of Health (AI072117 and AI067545 to A.W.G.; T32 AI060536 to J.A.B.; PN2 EY016586 to D.A.B. and M.L.D.; P30 CA016087 for cell sorting; and R24 AI072073 (National Institute of Allergy and Infectious Diseases) to the ImmGen Consortium), the Pew Scholars program (A.W.G.) and the Cancer Research Institute (A.W.G. and V.M.).

Author information





J.A.B. did experiments, designed studies, analyzed data and wrote the manuscript; J.K. sorted cell subsets and analyzed data; A.D. analyzed data and edited the manuscript; D.A.B., V.M. and M.L.D. designed and did early infection experiments, analyzed data and contributed to writing the manuscript; E.Y. sorted cell subsets; and A.W.G. designed studies, analyzed data and wrote the manuscript.

Corresponding author

Correspondence to Ananda W Goldrath.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

A list of members and affiliations appears at the end of the paper.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7, Tables 2–4 and Note (PDF 3722 kb)

Supplementary Table 1

Gene expression values for gene lists defined by clusters I-X. (XLSX 13917 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Best, J., Blair, D., Knell, J. et al. Transcriptional insights into the CD8+ T cell response to infection and memory T cell formation. Nat Immunol 14, 404–412 (2013).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing