Crosstalk Between Adaptive and Innate Immune Cells Leads to High Quality Immune Protection at the Mucosal Borders

  • Hilde CheroutreEmail author
  • Yujun Huang
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 785)


Mucosal effector memory CD8 T cells are located at the epithelium and have a heightened and immediate effector function. By contrast, central memory T cells reside within lymphoid tissues and require proliferation and differentiation to become effector cells that migrate to epithelial surfaces. The accumulation of effector memory T cells at the pathogen entry site(s) is essential for protective immunity, but the mechanisms that drive the differentiation of memory cell subsets are poorly understood. We recently showed that CD8αα, induced selectively on the most highly activated primary CD8αβ T cells, together with its ligand, the thymic leukemia (TL) antigen, induced on mucosal antigen-presenting cells and constitutively expressed on intestinal epithelial cells (IEC), serve as key components to mediate the selective accumulation of the fittest effector cells to form mucosal effector memory T cells. Therefore, the generation of mucosal effector memory is controlled by an innate-adaptive crosstalk that provides for host defense at the body’s largest interface.


Protective immunity Effector memory CD8 T cells Central memory CD8 T cells TCR affinity CD8αα Thymic leukemia antigen TL Mucosal dendritic cells Mucosal epithelium 


  1. 1.
    Cheroutre H, Madakamutil L. Mucosal effector memory T cells: the other side of the coin. Cell Mol Life Sci. 2005 Dec;62(23):2853–66.PubMedCrossRefGoogle Scholar
  2. 2.
    Masopust D, Vezys V, Marzo AL, Lefrancois L. Preferential localization of effector memory cells in nonlymphoid tissue. Science. 2001 Mar 23;291(5512):2413–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Masopust D, Vezys V, Wherry EJ, Barber DL, Ahmed R. Cutting edge: gut microenvironment promotes differentiation of a unique memory CD8 T cell population. J Immunol. 2006 Feb 15;176(4):2079–83.PubMedGoogle Scholar
  4. 4.
    Jiang X, Clark RA, Liu L, Wagers AJ, Fuhlbrigge RC, Kupper TS. Skin infection generates non-migratory memory CD8+ T(RM) cells providing global skin immunity. Nature. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. 2012 Mar 8;483(7388):227–31.Google Scholar
  5. 5.
    Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature. 1999 Oct 14;401(6754):708–12.PubMedCrossRefGoogle Scholar
  6. 6.
    Wolint P, Betts MR, Koup RA, Oxenius A. Immediate cytotoxicity but not degranulation distinguishes effector and memory subsets of CD8+ T cells. J Exp Med. [Research Support, Non-U.S. Gov’t]. 2004 Apr 5;199(7):925–36.Google Scholar
  7. 7.
    Huang Y, Park Y, Wang-Zhu Y, Larange A, Arens R, Bernardo I, et al. Mucosal memory CD8(+) T cells are selected in the periphery by an MHC class I molecule. Nat Immunol. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. 2011 Nov;12(11):1086–95.Google Scholar
  8. 8.
    Ellmeier W, Sunshine MJ, Losos K, Hatam F, Littman DR. An enhancer that directs lineage-specific expression of CD8 in positively selected thymocytes and mature T cells. Immunity. 1997 Oct;7(4):537–47.PubMedCrossRefGoogle Scholar
  9. 9.
    Madakamutil LT, Christen U, Lena CJ, Wang-Zhu Y, Attinger A, Sundarrajan M, et al. CD8alphaalpha-mediated survival and differentiation of CD8 memory T cell precursors. Science. 2004 Apr 23;304(5670):590–3.PubMedCrossRefGoogle Scholar
  10. 10.
    Hershberg R, Eghtesady P, Sydora B, Brorson K, Cheroutre H, Modlin R, et al. Expression of the thymus leukemia antigen in mouse intestinal epithelium. Proc Natl Acad Sci U S A. 1990 Dec;87(24):9727–31.PubMedCrossRefGoogle Scholar
  11. 11.
    Wu M, van Kaer L, Itohara S, Tonegawa S. Highly restricted expression of the thymus leukemia antigens on intestinal epithelial cells. J Exp Med. 1991 Jul 1;174(1):213–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Hansen SG, Ford JC, Lewis MS, Ventura AB, Hughes CM, Coyne-Johnson L, et al. Profound early control of highly pathogenic SIV by an effector memory T-cell vaccine. Nature. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, Non-P.H.S.]. 2011 May 26;473(7348):523–7.Google Scholar
  13. 13.
    Hansen SG, Vieville C, Whizin N, Coyne-Johnson L, Siess DC, Drummond DD, et al. Effector memory T cell responses are associated with protection of rhesus monkeys from mucosal simian immunodeficiency virus challenge. Nat Med. 2009 Mar;15(3):293–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Belyakov IM, Isakov D, Zhu Q, Dzutsev A, Berzofsky JA. A novel functional CTL avidity/­activity compartmentalization to the site of mucosal immunization contributes to protection of macaques against simian/human immunodeficiency viral depletion of mucosal CD4+ T cells. J Immunol. 2007 Jun 1;178(11):7211–21.PubMedGoogle Scholar
  15. 15.
    Belyakov IM, Kuznetsov VA, Kelsall B, Klinman D, Moniuszko M, Lemon M, et al. Impact of vaccine-induced mucosal high-avidity CD8+ CTLs in delay of AIDS viral dissemination from mucosa. Blood. 2006 Apr 15;107(8):3258–64.PubMedCrossRefGoogle Scholar
  16. 16.
    Daucher M, Price DA, Brenchley JM, Lamoreaux L, Metcalf JA, Rehm C, et al. Virological outcome after structured interruption of antiretroviral therapy for human immunodeficiency virus infection is associated with the functional profile of virus-specific CD8+ T cells. J Virol. 2008 Apr;82(8):4102–14.PubMedCrossRefGoogle Scholar
  17. 17.
    Letvin NL, Walker BD. Immunopathogenesis and immunotherapy in AIDS virus infections. Nat Med. 2003 Jul;9(7):861–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Vogel TU, Reynolds MR, Fuller DH, Vielhuber K, Shipley T, Fuller JT, et al. Multispecific vaccine-induced mucosal cytotoxic T lymphocytes reduce acute-phase viral replication but fail in long-term control of simian immunodeficiency virus SIVmac239. J Virol. 2003 Dec;77(24):13348–60.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Division of Developmental ImmunologyLa Jolla Institute for Allergy & ImmunologySan DiegoUSA

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