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    Immunology Cell Identity Markers

    Adaptive Immunity

    Adaptive immune responses are mediated by cellular (lymphocytes) effectors, soluble (cytokines) effectors, and humoral (plasma cell-derived antibodies) effectors. Versatility and memory are the two main distinguishing properties of the adaptive arm of the immune system. Versatility is underscored by genetic recombination mechanisms which ensure the expression of immune receptors with high specificity for antigen recognition in T and B lymphocytes. Immune memory results from the persistence of long lived lymphocytes with antigen specific receptors and antibody-secreting plasma cells, which are able to mount a rapid immune response upon re-stimulation.


    T cell subsets B cell Subsets

    Adaptive cellular mediators: functions and markers

    T Cell Subsets Function Markers

    Naïve T lymphocytes

    CD4+ T lymphocytes

    CD8+ T lymphocytes

    Mature T lymphocytes present in the blood and lymphoid organs without previous antigen interaction and thus inactive. Interaction with peptides presented through cells of the innate immune system, such as dendritic cells serving as antigen presenting cells, leads to T cell activation.

    CD45RA, CD62L, CCR7, CD27, CD28, CD25

    Effector T lymphocytes

    Cytotoxic T lymphocytes

    Helper T lymphocytes

    Foxp3 regulatory T lymphocytes

    Once activated, naïve CD4+ and CD8+ T lymphocytes generate different cell subsets.
    CD8+ subsets: Tc1 and Tc2
    CD4+ subsets: Th1, Th2, Th17 and Treg (Foxp3)


    Activated T cells perform cytotoxic functions via two main mechanisms:

    Cell-mediated- via cytotoxic CD8+ T cell induced lysis of damaged cells (infected or transformed)

    Soluble factors-mediated- via CD4+ T helper cell dependent release of cytokines that are toxic to infected cells or promote the activity of other immune cells (e.g., increase of antibody production and activity of NK cells)

    CD69, CD25, CD45RO, OX40, 4-1BBL, CD95, Granzyme B, Perforin, CD44

    Memory T cell

    Following exposure to an antigen, a small subset of effector T cells differentiate into memory cells and remain for years in peripheral lymphoid and non-lymphoid tissues. Memory T cells maintain their antigen specificity and help to amplify the immune response during antigen re-exposure. Memory T cells conform a heterogeneous population consisting of effector and central memory subsets. Some relevant markers include CCR7, CD62L, CD45RO, CD45RA, CD95, CD127, CD28 and Granzyme B.

    CD4 expression in human T cells ICC Intracellular perforin expression in CD8 T cells ICC

    CD4 was detected in immersion fixed human T cells using 2 μg/mL Goat Anti-Human CD4 Antigen Affinity-purified Polyclonal Antibody (Catalog #AF-379-NA) for 3 hours at room temperature. Cells were stained (red) and counterstained (green). View our protocol for Fluorescent ICC Staining of Cells on Coverslips.

    Immunocytochemistry/Immunofluorescence: Perforin Antibody (deltaG9) [NBP1-45774] - Isolated CD8 T-cells showing intracellular perforin (green).

    T cell subsets: humoral markers

    In addition to the use of CD markers for the identification of T cell subsets, various effector molecules specifically produced and secreted by T cells may facilitate their identification. Several types of cytokines are released from T cell subsets and may play both pro- and anti-inflammatory roles. Cytokines modulate the activity of T and B cells by influencing their growth, mobility and differentiation.


    T Cell Subsets Effector Molecules

    Th1

    IFN-gamma, TNF-alpha, IL-2, Lymphotoxin

    Th2

    IL-4, IL-5, IL-10, IL-13

    Th17

    IL-17, IL-21, IL-22, IL-25, IL-26

    Treg

    IL-10, TGF-beta

    T (CTL)

    Perforin, Granzymes, IFN-gamma, TNF-alpha, TNF-beta


    γδ T and NK T cells bridge innate and adaptive immunity

    γδ T cells comprise a relatively small subset of T cells (up to 5% of peripheral blood mononuclear cells). Similar to conventional T cells the smaller subset of γδ T cells is thymus derived, but differs in T cell receptor (TCR) composition, expressing a γδ heterodimer rather than an αβ TCR. γδ T cells may be found in peripheral blood and associated with epithelial tissues, where they play a role in innate immunity recognizing infectious antigens and tumor cells. γδ T cells express natural killer receptors and TCRs, thereby connecting both arms of immunity.


    γδ T types Function Effector molecules and markers

    Vδ1

    Mainly found in mucosal epithelium where they provide immune defense against infections and transformed cells

    IL-10

    Vδ2

    Predominant subset of peripheral γδ T cells which serve as antigen presenting cells (APCs)

    MHCII (HLA-DR), CD80, CD86

    Vδ3

    Not frequently found in blood but may be present in organs (e.g., liver), and may promote maturation of APCs

    MHCII (HLA-DR), CD56, CD161, NKG2D


    Natural Killer T cells (NKT) represent a small subtype of circulating T lymphocytes that are functionally similar to both NK and T cells. NKT cells diverge from conventional T cells in TCR expression and recognize CD1d associated lipid antigens. Type I NKT cells represent the more prevalent subset and are characterized by the expression of TCRs with an invariant alpha chain (Vα14–Jα18 ). NKT cells may also be identifiable by expression of CD161, Ly49, NKG2 and CD3 as well as CD44 and CD122 upon activation.



    Gamma Delta T and NK T cells bridge innate and adaptive immunity


    Cells of the Innate and Adaptive Immune System
    Cells of the innate immunity branch provide a rapid response to non-self antigens, in contrast cells of the adaptive immunity branch provide a slower but highly specific response. Several cell subsets, including γδ T cells and NKT cells, connect both branches of immunity because they express receptors similar to those in conventional B and T cells. Even though the specificity of these receptor is limited, the response to specific non-self antigens is prompt.


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    B cell subsets

    Knowledge about the role of B cells in immunity continues to expand. Traditionally, B cells have been recognized for their unique capacity to produce antibodies, however identification of B cell subtypes with unique functions and localization have clarified B cell contributions to both adaptive and innate immunity. Recently, B cells have been shown to participate in various antibody-independent roles in immunity including:

    • Antigen presentation
    • Cytokine production
    • Modulating the response of other immune cells (e.g., T cells)
    • Tissue repair


    B cell subsets: functions and markers

    Adaptive cellular mediators Location and Function Markers

    Long-lived Follicular B cells

    Mature B cells present in secondary lymphoid tissues which may give rise to short-lived plasma cells, antibody-secreting plasma cells, and memory B cells.

    Mice: CD23, CD21, CD1d, CXCR5

    Human: CD23, CD21, CXCR5

    Plasmablast: CD138 (mice), CD38, CD27

    Plasma cells: CD38 (human), CD27, CD138 (mice)

    Innate cellular mediators

    Splenic Marginal Zone B cells

    Mature B cells that interface the circulatory and lymphatic tissues. Provide rapid defense against blood pathogens. IgM and IgG3 antibody responses are elicited by interactions between bacterial antigens and B cell receptors (BCRs) or Toll-like receptors (TLRs).

    Mice: CD21, CD1d, CD9, CD35, CD80, CD86

    Human: IRTA1, IRTA2, CD1c, CD27, CD21

    B1 cells

    Mature B cell subset present in tissues (e.g., intestine, peritoneal cavity). Responsible for IgM and IgG3 antibody responses following exposure to bacterial antigens and to polysaccharide antigens. Derived from the fetal liver and produce the majority of natural low-affinity IgM antibodies as well as antigen-specific antibodies.

    Mice:  CD5, CD43, IL-5R, B220, CD9

    Human: CD20, CD27, CD43, CD5

    Additional markers include the pan B cell marker CD19.



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    Learn about B Cell Developmental Markers

    Select References

    Baumgarth N. (2016). B-1 Cell Heterogeneity and the Regulation of Natural and Antigen-Induced IgM Production. Frontiers in immunology, 7, 324. doi:10.3389/fimmu.2016.00324

    Bonilla, F. A., & Oettgen, H. C. (2010). Adaptive immunity. Journal of Allergy and Clinical Immunology. https://doi.org/10.1016/j.jaci.2009.09.017

    Cerutti, A., Cols, M., & Puga, I. (2013). Marginal zone B cells: Virtues of innate-like antibody-producing lymphocytes. Nature Reviews Immunology. https://doi.org/10.1038/nri3383

    Croft, M., So, T., Duan, W., & Soroosh, P. (2009). The significance of OX40 and OX40L to T-cell biology and immune disease. Immunological Reviews. https://doi.org/10.1111/j.1600-065X.2009.00766.x

    Garraud, O., Borhis, G., Badr, G., Degrelle, S., Pozzetto, B., Cognasse, F., & Richard, Y. (2012). Revisiting the B-cell compartment in mouse and humans: More than one B-cell subset exists in the marginal zone and beyond. BMC Immunology. https://doi.org/10.1186/1471-2172-13-63

    Golubovskaya, V., & Wu, L. (2016). Different subsets of T cells, memory, effector functions, and CAR-T immunotherapy. Cancers. https://doi.org/10.3390/cancers8030036

    Hatzivassiliou, G., Miller, I., Takizawa, J., Palanisamy, N., Rao, P. H., Iida, S., … Dalla-Favera, R. (2001). IRTA1 and IRTA2, novel immunoglobulin superfamily receptors expressed in B cells and involved in chromosome 1q21 abnormalities in B cell malignancy. Immunity. https://doi.org/10.1016/S1074-7613(01)00109-1

    Ikeda, J. ichiro, Kohara, M., Tsuruta, Y., Nojima, S., Tahara, S., Ohshima, K., … Morii, E. (2017). Immunohistochemical analysis of the novel marginal zone B-cell marker IRTA1 in malignant lymphoma. Human Pathology. https://doi.org/10.1016/j.humpath.2016.09.011

    Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001. General properties of armed effector T cells. Available from: https://www.ncbi.nlm.nih.gov/books/NBK27149/

    Liao, C. M., Zimmer, M. I., & Wang, C. R. (2013). The functions of type I and Type II Natural Killer T cells in inflammatory bowel diseases. Inflammatory Bowel Diseases. https://doi.org/10.1097/MIB.0b013e318280b1e3

    Oliveira, J. B. (2014). Marginal zone B-cell dysfunction in ALPS. Blood. https://doi.org/10.1182/blood-2014-07-585935

    Rothstein, T. L., Griffin, D. O., Holodick, N. E., Quach, T. D., & Kaku, H. (2013). Human B-1 cells take the stage. Annals of the New York Academy of Sciences. https://doi.org/10.1111/nyas.12137

    Sanz, I., Wei, C., Lee, F. E. H., & Anolik, J. (2008). Phenotypic and functional heterogeneity of human memory B cells. Seminars in Immunology. https://doi.org/10.1016/j.smim.2007.12.006

    Seino, K., & Taniguchi, M. (2005). Functionally distinct NKT cell subsets and subtypes: The Journal of Experimental Medicine. https://doi.org/10.1084/jem.20051600

    Won, W.-J., & Kearney, J. F. (2002). CD9 Is a Unique Marker for Marginal Zone B Cells, B1 Cells, and Plasma Cells in Mice. The Journal of Immunology. https://doi.org/10.4049/jimmunol.168.11.5605

    Wu, Y. L., Ding, Y. P., Tanaka, Y., Shen, L. W., Wei, C. H., Minato, N., & Zhang, W. (2014). γδ T cells and their potential for immunotherapy. International Journal of Biological Sciences. https://doi.org/10.7150/ijbs.7823

    Zouali, M., & Richard, Y. (2011). Marginal zone B-cells, a gatekeeper of innate immunity. Frontiers in Immunology. https://doi.org/10.3389/fimmu.2011.00063