CD57 Human

What is CD57 and which human cell populations express it?

CD57 (also known as HNK-1, LEU-7, or L2) is a cell-surface marker primarily expressed on specific subsets of natural killer (NK) cells and T-lymphocytes. It serves as an important phenotypic marker used to identify terminally differentiated cells with altered functional properties. CD57 is most commonly found on:

• A subset of natural killer (NK) cells, particularly the mature CD56dim NK cell population

• Terminally differentiated CD8+ T cells, especially within the effector memory re-expressing CD45RA (TEMRA) subset

• A subset of follicular helper T cells (TFH) in humans (but not in mice)

• Some CD4+ T cells, particularly those with cytotoxic properties

CD57 expression increases with age and chronic antigen stimulation, making it a valuable marker for understanding immunological aging and chronic immune responses .

What does CD57 expression indicate about human lymphocyte function?

CD57 expression on human lymphocytes indicates significant functional specialization and developmental status:

• On NK cells: CD57 marks mature NK cells with enhanced cytotoxic potential and memory-like features, though with reduced proliferative capacity

• On CD8+ T cells: CD57 typically identifies terminally differentiated "senescent" cells with:

  • Reduced proliferative capacity

  • High cytotoxic potential

  • Altered cytokine production profiles

  • Shortened telomeres

  • Increased susceptibility to activation-induced cell death

The functional significance of CD57 varies between cell types. While CD57+ cells generally show reduced proliferation, they display potent effector functions, particularly cytotoxicity. This creates an interesting paradox where cells considered "senescent" maintain important immune surveillance and protective roles .

How are CD57+ cells isolated and analyzed in experimental settings?

Isolation and analysis of CD57+ cells typically follow these methodological approaches:

• Flow cytometry: The most common method using fluorochrome-conjugated anti-CD57 antibodies in combination with other lineage and differentiation markers

• Magnetic cell separation (MACS): For isolating pure CD57+ or CD57- populations for functional studies

• Analysis protocols:

  • Surface marker combinations (CD8/CD57, CD56/CD57, CD4/CD57)

  • Additional markers (CD27, CD28, CCR7, CD45RA) to define differentiation status

  • Intracellular cytokine staining for functional characterization

When designing experiments, researchers should consider that CFSE labeling may be toxic to CD57+ cells, potentially causing false interpretations about their proliferative capacity. Studies have shown that CD8hiCD57+ cells exhibit significantly reduced viability in the presence of CFSE, with a fourfold decrease in live cells and threefold increase in dead cells .

How does CD57 contribute to defining functional subsets of CD8+ T cells?

CD57 provides critical functional segregation within the CD8+ T EMRA (CD45RA+/CCR7-) cell population:

• CD57+ T EMRA cells:

  • Truly terminally differentiated state

  • Limited proliferative capacity

  • Shorter telomeres

  • Lower sensitivity to antigen stimulation

  • High immediate cytotoxic potential

  • More susceptible to cell death after stimulation

• CD57- T EMRA cells:

  • "Young" TEMRA subset with differentiation plasticity

  • Higher proliferative capacity

  • Longer telomeres

  • Higher sensitivity to antigenic stimulation

  • Comparable cytotoxic function to CD57+ cells

  • Can differentiate into other phenotypes including gaining CD57

This distinction is particularly relevant for monitoring antigen-specific cytotoxic T lymphocytes (CTLs) in patients after hematopoietic stem cell transplantation (HSCT). While both CD57+ and CD57- subsets showed comparable peptide-specific cytotoxicity in CMV-specific responses, CD57- cells demonstrated significantly higher proliferative capacity and cytokine production .

What methodological considerations are important when studying CD57+ cell proliferation?

Contradictory findings regarding CD57+ T cell proliferation in the literature can be explained by several methodological factors:

• Cell culture conditions:

  • CD57+ cells show severely impaired proliferation in fetal calf serum (FCS)

  • Human AB serum significantly improves CD57+ cell proliferation

• Cytokine supplementation:

  • High levels of IL-2 are required for proper CD57+ cell proliferation

  • Low cytokine conditions may result in minimal proliferation

• Stimulation method:

  • Plate-bound anti-CD3 (OKT3) provides stronger stimulation than peptides or bacterial superantigens

  • Observation period (5-8 days vs. 48h) impacts detection of proliferation

• CFSE labeling toxicity:

  • CFSE exhibits dose-dependent inhibition of CD8hiCD57+ cell proliferation

  • This toxicity is primarily through non-apoptotic mechanisms

  • CFSE toxicity particularly affects CD57+ cells but not CD57- cells

These findings resolve the paradox in literature where CD57+ cells were reported to be incapable of division yet form stable, antigen-specific in vivo expansions. Researchers studying CD57+ cell proliferation should carefully select culture conditions and avoid CFSE labeling when possible .

How does CD57 expression correlate with cytokine production profiles?

CD57 expression significantly impacts cytokine production profiles in human lymphocytes:

• Early cytokine production (within 4 days of stimulation):

  • CD8hiCD57+ cells produce high levels of IFN-γ and TNF-α

  • CD8hiCD57- cells show lower cytokine production

• Late cytokine production (>4 days of stimulation):

  • CD8hiCD57+ cells uniquely produce significant amounts of IL-5

  • IL-5 production increases with time and depends on anti-CD3 signal strength and IL-2 concentration

  • By day 6, IL-5 levels become second only to IFN-γ in CD8hiCD57+ cultures

• Distinct CD57+ cell populations:

  • Intracellular cytokine staining reveals that different CD8hiCD57+ cells produce IL-5 versus IFN-γ

  • This indicates functional heterogeneity within the CD57+ population

This unexpected IL-5 production by CD8hiCD57+ cells suggests these cells may have more diverse immunoregulatory roles than previously recognized, potentially including modulation of eosinophil responses .

What is the relationship between CD57, STAT3 signaling, and T cell function?

STAT3 signaling plays a critical role in regulating CD57+ T cell development and function:

• TFH cells and CD57:

  • A subset of human follicular helper T cells (TFH) expresses CD57

  • CD57+ TFH cells are universally PD-1hi

  • Compared to CD57- PD-1hi TFH cells, CD57+ cells express little IL-21 or IL-10

  • CD57 expression on TFH cells marks cytotoxicity transcriptional signatures

• STAT3 regulation:

  • CD4+ T cell cytotoxicity is STAT3-dependent

  • TFH formation requires STAT3 signaling

  • Once formed, PD-1hi cells become unresponsive to STAT3

  • Changes in blood and germinal center cytotoxicity might be affected by alterations in STAT3 signaling

• PD-1 modulation:

  • Therapeutic modulation of PD-1 may impact CD57+ cell function

  • High PD-1 expression is observed on CD8+ T cells after chronic antigen stimulation and marks clonal exhaustion

These findings suggest that targeting STAT3 signaling pathways or PD-1 through immunotherapies may have significant impacts on CD57+ T cell populations and their functions .

How is CD57 testing used in Lyme disease research and diagnosis?

CD57 testing has been investigated as a potential biomarker in Lyme disease management:

• Rationale: Research from 2001 by hematologist Raphael Stricker found that patients with chronic Lyme disease had significantly decreased CD57 NK cell counts compared to control groups

• Diagnostic potential: Some Lyme practitioners recommend the CD57 test to help confirm a Lyme disease diagnosis when other tests are inconclusive

• Treatment monitoring: CD57 levels reportedly increased to normal range after completing antibiotic therapy, suggesting potential utility in monitoring treatment efficacy

• Limitations: While CD57 testing offers additional information, it should be interpreted in the clinical context rather than as a standalone diagnostic tool

The utility of CD57 testing in Lyme disease stems from the notoriously difficult diagnosis of chronic Lyme, where common tests like ELISA, Western Blot, PCR, and cultures show poor sensitivity. More than 50% of people with Lyme-related symptoms don't meet standard diagnostic criteria, highlighting the need for additional biomarkers .

What is the significance of CD57 in monitoring immune responses following transplantation?

CD57 expression provides valuable insights for monitoring immune reconstitution and pathogen-specific responses after transplantation:

• Predictor of persistent immunity:

  • Absence of CD57 expression on CMV-specific T cells predicts long-term persistence of donor-derived cells in the recipient

  • CD57 negativity correlates with protection against viral reactivation after hematopoietic stem cell transplantation (HSCT)

• Monitoring tool:

  • CD57 serves as a singular marker that may reduce the complexity of phenotypic panels

  • It uniquely distinguishes terminally differentiated cells from those with proliferative potential

• Functional implications:

  • CD57- CMV-specific T EMRA cells show higher peptide sensitivity and proliferative capacity

  • Both CD57+ and CD57- CMV-specific T cells display comparable cytotoxicity

  • CD57- cells may provide more sustainable immune protection

These findings suggest that monitoring CD57 expression on pathogen-specific T cells after transplantation may help predict long-term immunity and guide immunotherapeutic interventions .

How do CD57+ and CD57- cells differ in telomere length and replicative potential?

Telomere length analysis reveals significant differences between CD57+ and CD57- lymphocyte subsets:

• Absolute telomere length:

  • CD57+ T EMRA cells have substantially shorter telomeres than CD57- T EMRA cells

  • This difference in telomere length correlates with their contrasting replicative capacity

• Methodological approaches:

  • Quantitative PCR with a pre-amplification step allows telomere length analysis from as few as 50 cells

  • Southern blot hybridization can be used for validation using 1μg genomic DNA isolated from 2×10^6 cells

  • Reference controls include the human T cell leukemia cell line 1301 (long telomeres) and breast cancer cell line cal51 (short telomeres)

• Proliferative implications:

  • Shortened telomeres in CD57+ cells correlate with their reduced proliferative capacity

  • CD57- cells with longer telomeres show greater proliferative potential and differentiation plasticity

  • Upon stimulation, CD57- T EMRA cells can partially differentiate into effector memory cells and gain CD57 expression

These telomere findings provide a molecular basis for the functional differences between CD57+ and CD57- cells and support the concept that CD57- cells represent a less differentiated stage with greater regenerative potential .

What are the emerging areas of research on CD57 in human immunology?

Several promising research directions are emerging in the field of CD57 biology:

• Transcriptional profiling:

  • Comprehensive analysis of gene expression differences between CD57+ and CD57- subsets

  • Defining transcriptional signatures that explain functional differences

• Aging and senescence:

  • Further exploration of CD57 as a biomarker of immunological aging

  • Understanding how CD57+ cells contribute to immunosenescence

• Memory-like features:

  • Investigation of memory-like properties of CD57+ NK cells

  • Understanding how CD57+ cells maintain long-term immune surveillance

• Differential response to immunotherapies:

  • Studying how CD57+ versus CD57- cells respond to checkpoint inhibitors

  • Developing strategies to modulate CD57+ cell function in disease states

• Resolution of functional contradictions:

  • Further clarification of the paradox between "senescence" markers and functional importance

  • Understanding the context-dependent functionality of CD57+ cells

These research directions may lead to innovative strategies for protection against immunological aging and various chronic diseases .

How might we better understand the relationship between CD57, CMV infection, and human immunological aging?

The complex relationship between CD57 expression, cytomegalovirus (CMV) infection, T-cell receptor (TCR) repertoire, and physiological aging remains incompletely understood:

• Research challenges:

  • Studies often use different antibody panels to define T-cell subsets

  • Statistical power has been limited in many studies

  • Difficulty separating effects of infection versus aging itself

• Key questions for future research:

  • Does loss of immunity in elderly result from cumulative consequences of memory inflation due to persistent CMV infection?

  • How does attrition of naïve T-cells contribute to this process?

  • What is the causal relationship between CMV, CD57 expression, and functional immune decline?

• Methodological approaches:

  • Longitudinal studies tracking CD57 expression over time in CMV+ and CMV- individuals

  • TCR repertoire analysis in CD57+ and CD57- subsets

  • Systems biology approaches integrating multiple parameters of immune function

This research area has significant implications for understanding immunosenescence and developing strategies to maintain immune function throughout aging .