Review Article | Published:

Human memory T cells: generation, compartmentalization and homeostasis

Nature Reviews Immunology volume 14, pages 2435 (2014) | Download Citation


Memory T cells constitute the most abundant lymphocyte population in the body for the majority of a person's lifetime; however, our understanding of memory T cell generation, function and maintenance mainly derives from mouse studies, which cannot recapitulate the exposure to multiple pathogens that occurs over many decades in humans. In this Review, we discuss studies focused on human memory T cells that reveal key properties of these cells, including subset heterogeneity and diverse tissue residence in multiple mucosal and lymphoid tissue sites. We also review how the function and the adaptability of human memory T cells depend on spatial and temporal compartmentalization.

Key points

  • Most of our understanding of memory T cell generation, function and maintenance comes from mouse studies, which cannot recapitulate the exposure to diverse antigens and microbiota that occurs over many decades in humans.

  • Memory T cell frequency dynamically changes throughout the human lifetime and this can be divided into three phases: memory generation, memory homeostasis and immunosenescence.

  • CD45RO+CD45RA T cells comprise diverse memory T cell subsets, including central memory T (TCM) cells, effector memory T (TEM) cells, stem cell memory T (TSCM) cells and tissue-resident memory T (TRM) cells, which are heterogeneous in their generation, distribution and function.

  • Memory T cells that are specific for antigens from ubiquitous pathogens and possibly from endogenous flora are generated early in life and are preferentially compartmentalized at the sites of infection throughout adulthood.

  • Human memory T cells in diverse tissue sites are homeostatically maintained, potentially through tonic T cell receptor signalling, and can show extensive cross reactivity and can persist for decades.

  • The induction of memory CD4+ and CD8+ T cells through vaccination can enhance protection against pathogens, and might be improved by considering the anatomical location and the timing of vaccine administration during the early stages of life.

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The authors wish to thank J. Thome and D. Turner for a critical review of the manuscript. D.L.F. is supported by US National Institutes of Health grants AI106697, AI100119 and AI083022.

Author information


  1. Columbia Center for Translational Immunology and Department of Microbiology and Immunology, Columbia University Medical Center, 650 West 168th Street, BB1501, New York, New York 10032, USA.

    • Donna L. Farber
    •  & Naomi A. Yudanin
  2. Department of Surgery, Columbia University Medical Center, 650 West 168th Street, BB1501, New York 10032, USA.

    • Donna L. Farber
  3. National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

    • Nicholas P. Restifo


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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Donna L. Farber.


Memory homeostasis

The stable maintenance of memory T cell numbers through multiple mechanisms, including continuous turnover, responses to homeostatic cytokines and non-cognate T cell receptor interactions.


The decreased function of the immune system with age. In particular, the number of naive T cells decreases as thymic function decreases.


(Enzyme-linked immunosorbent spot). An antibody capture-based method for enumerating specific CD4+ and CD8+ T cells that secrete a particular cytokine (often interferon-γ).

MHC tetramer

A method of visualizing antigen-specific T cells by flow cytometry. Typically, four MHC molecules with their associated peptides are held together by streptavidin (that has four binding sites for biotin), which is attached to the tail of the MHC molecule. These four peptide—MHC complexes (tetramers) can bind to peptide-specific T cell receptors. The streptavidin molecules are often labelled with a fluorochrome so that binding can be assessed by flow cytometry.


Regions of highly repetitive DNA at the end of linear eukaryotic chromosomes. They protect the ends of the chromosome from shortening following replication.

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