Skip to main content

Thank you for visiting nature.com. 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.

  • Letter to the Editor
  • Published:

Letter to Editor

Tracking cytotoxic potential in vivo

Cellular & Molecular Immunology volume 12, pages 505–507 (2015)Cite this article

Infection of a host results in the activation, proliferation and differentiation of rare naive antigen-specific CD8+ T cells. Appropriate initiation of the CD8+ T-cell response occurs when the lymphocyte interacts with its cognate antigen presented by MHC class I on antigen-presenting cells within secondary lymphoid organs. During this process, the antigen-presenting cells actively shape the early CD8+ T-cell response by their expression of costimulatory molecules and secretion of cytokines. This results in the exponential expansion of antigen-specific CD8+ T cells. Subsequently, the majority of the antigen-specific CD8+ T cells die during contraction, while a small proportion of the antigen-specific CD8+ T cells survive to form the memory CD8+ T-cell population. Numerous studies have shown that the effector CD8+ T-cell population found at the peak of the immune response is extremely heterogeneous with each subpopulation having different memory potential.1 Heterogeneity within the effector CD8+ T-cell population can be resolved by a combination of IL-7Rα/CD127 and KLRG1 expression to distinguish terminal effector CD8+ T cells with a shorter half-live (IL-7Rα/CD127low KLRG1high; SLECs) or effector CD8+ T cells with a longer half-life and greater memory potential (IL-7Rα/CD127high KLRG1low; MPECs).2 Further heterogeneity within the MPEC population can be revealed by CD62L and CD103 expression to identify CD62Lhigh central-memory precursors (Tcm MPECs), CD62Llow effector-memory precursors (Tem MPECs) and CD103high tissue-resident memory cells (Trm) MPECs.3,4 However, it has been thought that each effector CD8+ T-cell subpopulation passes through a requisite cytotoxic effector stage.5 In this issue of Cellular and Molecular Immunology, Sarkar and colleagues provide further in vivo evidence that each effector CD8+ T-cell subpopulation, regardless of memory potential, passes through a requisite stage of high cytotoxic (CTL) activity that is tuned by the local immune microenvironment.6

Our understanding of the CD8+ T-cell response was been highly dependent on ex vivo analysis of responding CD8+ T cells in order to understand their biology. Slowly, we have increased the arsenal of in vivo assays to assess their activation, differentiation, functionality and localization. Importantly, these assays have both confirmed and challenged what the field has found using ex vivo assays. In this issue of Cellular and Molecular Immunology, Sarkar and colleagues6 further enhance our ability to analyze cellular populations in vivo by developing a staining method to track both the in vivo phenotype and CTL effector function of responding CD8+ T cells. To stain CD8+ T cells in vivo, Sarkar and colleagues6 administered monoclonal antibodies intravenously for 1–2 h prior to tissue collection allowing the diffusion of the monoclonal antibodies into the tissue to effectively stain the entire CD8+ T-cell population.6 This staining protocol recapitulated the phenotype of effector CD8+ T cells observed during the acute phase of lymphocytic choriomeningitis virus (LCMV) using standard ex vivo analysis. Yuzefpolskiy et al. couple this traditional in vivo staining assay with in vivo cell surface expression of CD107a/b,6 which marks lytic granule release (degranulation) within T-cell populations. Using this novel in vivo degranulation assay to assess CTL effector function, Yuzefpolskiy et al.6 confirm that early after infection both SLECs and MPECs have equivalent effector function and transition through a requisite CTL effector phase in vivo, consistent with previous ex vivo markers of effector function.7 Excitingly, Sarkar and colleagues'6 in vivo degranulation assay also contributes important new information to the field. First, they found that the CTL effector program was rapidly shut down within the lymph nodes.6 Second, at later time points (8 d.p.i.) after acute LCMV infection, the KLRG-1highCD8+ T cells (SLECs) had decreased CTL effector activity suggesting that SLECs in an antigen rich tissue may be more likely to undergo functional exhaustion and cell death.6 Thus, this work highlights that understanding the spatial location of effector CD8+ T cells has important implications in understanding effector versus memory differentiation.8,9

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

References

  1. Kaech SM, Cui W . Transcriptional control of effector and memory CD8+ T cell differentiation. Nat Rev Immunol 2012; 12: 749–761.

    Article  CAS  Google Scholar 

  2. Joshi NS, Kaech SM . Effector CD8 T cell development: a balancing act between memory cell potential and terminal differentiation. J Immunol 2008; 180: 1309–1315.

    Article  CAS  Google Scholar 

  3. Obar JJ, Lefrancois L . Early signals during CD8 T cell priming regulate the generation of central memory cells. J Immunol 2010; 185: 263–272.

    Article  CAS  Google Scholar 

  4. Sheridan BS, Pham QM, Lee YT, Cauley LS, Puddington L, Lefrançois L . Oral infection drives a distinct population of intestinal resident memory CD8+ T cells with enhanced protective function. Immunity 2014; 40: 747–757.

    Article  CAS  Google Scholar 

  5. Lefrancois L, Masopust D . The road not taken: memory T cell fate ‘decisions’. Nat Immunol 2009; 10, 369–370.

    Article  CAS  Google Scholar 

  6. Yuzefpolskiy Y, Baumann F, Kalia V, Sarkar S . Early CD8 T cell memory precursors exhibit potent in vivo degranulation. Cell Mol Immunol 2014; 12: 400–408.

    Article  Google Scholar 

  7. Obar JJ, Jellison ER, Sheridan BS, Blair DA, Pham QM, Zickovich JM et al. Pathogen-induced inflammatory environment controls effector and memory CD8+ T cell differentiation. J Immunol 2011; 187: 4967–4978.

    Article  CAS  Google Scholar 

  8. Jung YW, Rutishauser RL, Joshi NS, Haberman AM, Kaech SM . Differential localization of effector and memory CD8 T cell subsets in lymphoid organs during acute viral infection. J Immunol 2010; 185: 5315–5325.

    Article  CAS  Google Scholar 

  9. Kedzierska K, Stambas J, Jenkins MR, Keating R, Turner SJ, Doherty PC . Location rather than CD62L phenotype is critical in the early establishment of influenza-specific CD8+ T cell memory. Proc Natl Acad Sci USA 2007; 104: 9782–9787.

    Article  CAS  Google Scholar 

  10. Masopust D, Vezys V, Marzo AL, Lefrancois L . Preferential localization of effector memory cells in nonlymphoid tissue. Science 2001; 291: 2413–2417.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

JJO is supported by the Montana Agricultural Experiment State. Both JJO and BSS are supported by grants from the National Institutes of Health.

Author information

Authors and Affiliations

  1. Department of Microbiology & Immunology, Montana State University, Bozeman, MT, USA

    Joshua J Obar

  2. Department of Immunology, University of Connecticut Health Center, Farmington, CT, USA

    Brian S Sheridan

Authors
  1. Joshua J Obar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brian S Sheridan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joshua J Obar.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Obar, J., Sheridan, B. Tracking cytotoxic potential in vivo. Cell Mol Immunol 12, 505–507 (2015). https://doi.org/10.1038/cmi.2014.69

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cmi.2014.69

Search

Advanced search

Quick links