Innate lymphoid cells (ILCs) are part of the innate immune system and play important roles in immune defense against microbes, regulation of adaptive immunity, and tissue remodeling and repair. ILCs contribute to tissue repair, tissue homeostasis, and metabolic homeostasis through their interactions with other immune and non-immune cells.

The ILC family can be divided into the non-cytotoxic ILCs (ILC1, ILC2, and ILC3), natural killer cells, and lymphoid tissue inducer cells (LTis). ILCs are primarily tissue-resident cells, especially at mucosal tissues and barrier sites, and their tissue residency is associated with unique tissue-specific transcriptional profiles. Compared to ILCs found in peripheral blood, tissue-resident ILCs display distinct phenotypes and functional properties. Human innate lymphoid cells have been characterized in various tissues using advanced single-cell techniques, revealing their heterogeneity and tissue-specific imprinting.

ILC1 subsets can share features with cytotoxic T cells and T cell subsets, making it important to distinguish between these cell types during analysis. ILCs are identified as lineage-negative cells using flow cytometry, with fluorescence minus controls and specific gating strategies to exclude NK cells and accurately define ILC populations. At mucosal surfaces, ILCs interact with epithelial cells to regulate mucosal immunity and immune cell recruitment. ILCs are classified into multiple cell subsets based on cell surface markers, transcription factor expression, and functional properties. They are involved in chronic inflammation and immune regulation and interact with regulatory T cells to control inflammation and maintain tissue homeostasis.

ILCs originate from progenitors in the bone marrow, and lti cells are a distinct subset involved in lymphoid tissue development. ILCs are distinguished from antigen-presenting and red blood cells during cell isolation and analysis to ensure accurate characterization. Group 2 innate lymphoid cells (ILC2s) and two innate lymphoid cells are important for tissue-specific immune responses. Transcription factor expression is critical in defining ILC cell type and T cell development. ILCs are among the innate immune cells involved in early immune responses and tissue remodeling, and the cells involved in these processes can be identified by their unique gene expression profiles.

Group 1 innate lymphoid cells (ILC1s) are a subset of immune cells that contribute to early defense responses and tissue homeostasis. Unlike adaptive immune cells, ILC1s lack antigen-specific receptors but share functional similarities with natural killer (NK) cells. A key feature of ILC1s is their expression of transcription factor T-bet and production of interferon-gamma (IFN-γ), which supports their role in type 1 immune responses.

Markers such as CD127, CD49a, and NKp46 help distinguish ILC1s from other ILC subsets and NK cells. However, marker expression can vary depending on tissue context and inflammatory signals, making phenotypic identification complex. Recent studies have explored the plasticity of ILC1s and their potential to transition between ILC states, highlighting the importance of using multiple markers for accurate classification.

Ongoing research continues to refine our understanding of ILC1 biology and its implications in infection, inflammation, and tissue repair.

CD127

CD127, the IL-7 receptor alpha chain, is a marker for identifying ILC1 innate lymphoid cells. These cells contribute to immune responses by producing cytokines and exhibiting cytotoxic activity. CD127+ ILC1s have been linked to antiviral defense by secretion of molecules like granulysin and perforin. In tumor microenvironments, they may influence immune surveillance and modulate inflammation. Their expression patterns and functional diversity across tissues suggest a role in shaping immune responses under stress or disease conditions, including chronic inflammation and cancer.

Figure 1. Flow Cytometry - Anti-CD127 antibody [EPR22835-249] (ab255816).

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CD161

CD161, encoded by the KLRB1 gene, is a surface marker found on ILC1 innate lymphoid cells. It is involved in immune regulation and has been observed in cytotoxic lymphocyte subsets across various tissues. CD161+ ILC1s may contribute to antiviral responses by promoting cytokine release and cytotoxic granule secretion. In tumor environments, CD161 expression can influence immune cell activation and interaction with CLEC2D-expressing cells. Blocking CD161 has shown potential to enhance anti-tumor activity, suggesting its relevance in immunotherapy strategies targeting innate immune pathways.

Figure 2. Immunocytochemistry/ Immunofluorescence - Anti-CD161 antibody [EPR26340-6] (ab302564).

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CD121a

CD121a, also known as IL-1 receptor type I, is expressed on ILC1 innate lymphoid cells and contributes to immune signaling pathways. Its presence supports cytokine responsiveness and may influence ILC1 activation in response to infection. CD121a+ ILC1s have been observed in mucosal tissues, where they participate in antiviral defense through interferon gamma production. In tumor settings, CD121a expression may modulate inflammation and immune cell recruitment. These features position CD121a as a marker of interest for studying innate immunity and potential therapeutic modulation.

Figure 3. Immunohistochemistry (Formalin/PFA-fixed paraffin-embedded sections) - Anti-IL1 Receptor I/IL-1R-1 antibody [EPR20150-241] - BSA and Azide free (Detector) (ab244859).

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T-bet

T-bet, a transcription factor encoded by the TBX21 gene, is a defining marker of ILC1 innate lymphoid cells. It regulates the expression of interferon gamma and supports the development of cytotoxic functions. T-bet+ ILC1s are involved in antiviral immunity by enhancing cytokine production and promoting tissue-specific responses. T-bet influences immune cell infiltration in tumor microenvironments and may contribute to anti-tumor activity. Its expression helps distinguish ILC1s from other ILC subsets, offering insights into innate immune regulation and potential therapeutic applications.

Figure 4. Immunohistochemistry (Formalin/PFA-fixed paraffin-embedded sections) - Anti-T-bet / Tbx21 antibody [EPR27094-16] (ab307193).

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Group 2 innate lymphoid cells (ILC2s) are key players in type 2 immune responses, particularly in mucosal tissues such as the lungs and intestines. These cells are identified by CD127, CRTH2, and GATA3 markers, and are known for producing cytokines like IL-5 and IL-13. Recent studies have highlighted the presence of TLR4+ ILC2 subsets, which show enhanced cytokine expression and may contribute to persistent inflammation in airway diseases.

ILC2s exhibit phenotypic plasticity, with subsets such as ILC2_c01 and ILC2_c02 showing distinct transcriptional profiles. The ILC2_c02 subset, enriched in inflammatory conditions, expresses higher levels of memory-associated markers and may represent a trained immunity phenotype. This evolving understanding of ILC2 markers and function supports ongoing efforts to refine immune profiling in chronic inflammatory diseases and explore therapeutic strategies targeting innate lymphoid cells.

CD127

CD127, the IL-7 receptor alpha chain, is a key marker for identifying ILC2 innate lymphoid cells. These cells are involved in type 2 immune responses and are active in mucosal tissues. CD127+ ILC2s contribute to defense against helminth infections by producing cytokines like IL-5 and IL-13. In airway inflammation, they are linked to allergic responses and tissue remodeling. Their presence and activity vary with environmental cues, making CD127 a useful marker for studying ILC2 function in both protective and pathological contexts.

Figure 5. Flow Cytometry - Anti-CD127 antibody [EPR22835-249] (ab255816).

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CD161

CD161, encoded by the KLRB1 gene, is expressed on subsets of ILC2 innate lymphoid cells and may influence their activation and migration. In helminth infections, CD161+ ILC2s contribute to parasite clearance by producing type 2 cytokines such as IL-5 and IL-13. These cells are also implicated in airway inflammation, where they may amplify allergic responses and tissue remodeling. CD161 expression can vary with environmental signals, suggesting a role in modulating ILC2 function across different mucosal sites.

Figure 6. Immunocytochemistry/ Immunofluorescence - Anti-CD161 antibody [EPR26340-6] (ab302564).

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CD121a

CD121a, also known as IL-1 receptor type I, is expressed on ILC2 innate lymphoid cells and plays a role in cytokine signaling. In helminth infections, CD121a+ ILC2s contribute to parasite clearance by promoting type 2 cytokine production. These cells are also active in airway inflammation, where they respond to epithelial-derived signals and influence allergic responses. CD121a expression may vary with tissue context and immune activation, making it a useful marker for studying ILC2 behavior in mucosal immunity and inflammatory conditions.

Figure 7. Immunohistochemistry (Formalin/PFA-fixed paraffin-embedded sections) - Anti-IL1 Receptor I/IL-1R-1 antibody [EPR20150-241] - BSA and Azide free (Detector) (ab244859).

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GATA3

GATA3 is a transcription factor that defines ILC2 innate lymphoid cells and regulates their development and function. It supports the production of type 2 cytokines such as IL-5 and IL-13, which are involved in clearing helminth infections and promoting tissue repair. In airway inflammation, GATA3+ ILC2s respond to epithelial signals and contribute to allergic responses. Their activity influences immune balance in mucosal tissues. GATA3 expression helps distinguish ILC2s from other ILC subsets, making it a valuable marker in studies of type 2 immunity.

Figure 8. Immunohistochemistry (Formalin/PFA-fixed paraffin-embedded sections) - Anti-GATA3 antibody [EPR16651] - ChIP Grade (ab199428).

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Group 3 innate lymphoid cells (ILC3s) are a distinct subset involved in mucosal immunity and tissue integrity. Characterized by the expression of RORγt and production of IL-22, ILC3s play a role in maintaining epithelial barrier function, especially in the gut. Common markers used to identify ILC3s include CD127, CD117, and NKp46, although marker expression can vary across tissues and inflammatory states.

Recent research has shown that ILC3s contribute to immune tolerance during infection by activating tissue-protective pathways. In mouse models, ILC3-derived IL-22 was necessary for epithelial homeostasis, even in the presence of IL-22-producing T cells. This highlights the context-dependent role of ILC3s in balancing immune responses and promoting recovery. Understanding ILC3 marker profiles and their functional diversity is helping researchers refine immune cell classification and explore new therapeutic approaches in inflammatory and infectious diseases.

CD127

CD127, the IL-7 receptor alpha chain, is a marker commonly used to identify ILC3 innate lymphoid cells. These cells are active in mucosal tissues and contribute to immune responses against extracellular pathogens. CD127+ ILC3s produce cytokines like IL-22, which support epithelial integrity and promote tissue remodeling. During infection, they help regulate inflammation and maintain barrier function. Their activity is context-dependent, varying with microbial exposure and immune status, making CD127 a useful marker for studying ILC3 roles in gut immunity and mucosal health.

Figure 9. Flow Cytometry - Anti-CD127 antibody [EPR22835-249] (ab255816).

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CD161

CD161, encoded by the KLRB1 gene, is expressed on ILC3 innate lymphoid cells and may influence their activation and migration. CD161+ ILC3s are involved in mucosal immunity, where they produce cytokines like IL-22 that support epithelial barrier integrity and promote tissue remodeling. These cells also contribute to defense against extracellular pathogens by responding to microbial signals and coordinating local immune responses. CD161 expression varies with environmental cues, making it a useful marker for studying ILC3 function in gut health and inflammation.

Figure 10. Immunocytochemistry/ Immunofluorescence - Anti-CD161 antibody [EPR26340-6] (ab302564).

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CD121a

CD121a, also known as IL-1 receptor type I, is expressed on ILC3 innate lymphoid cells and contributes to immune signaling in mucosal environments. CD121a+ ILC3s respond to IL-1 family cytokines, promoting the release of IL-22 and other mediators that support epithelial repair and barrier integrity. These cells play a role in defending against extracellular pathogens by coordinating local immune responses and maintaining tissue homeostasis. CD121a expression helps identify active ILC3 populations involved in inflammation, microbial sensing, and mucosal remodeling.

Figure 11. Immunohistochemistry (Formalin/PFA-fixed paraffin-embedded sections) - Anti-IL1 Receptor I/IL-1R-1 antibody [EPR20150-241] - BSA and Azide free (Detector) (ab244859).

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CD117

CD117, also known as c-Kit, is a surface receptor expressed on ILC3 innate lymphoid cells and plays a role in their development and function. CD117+ ILC3s contribute to mucosal immunity by producing IL-22, which supports epithelial repair and barrier integrity. These cells respond to microbial signals and help coordinate immune responses against extracellular pathogens. CD117 expression is associated with ILC3 activity in tissue remodeling and inflammation, making it a useful marker for studying innate immune responses in the gut and other mucosal site.

Figure 12. Flow Cytometry - Anti-c-Kit antibody [EPR25707-134] (ab283653).

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IL-23R

IL-23R, the interleukin-23 receptor, is expressed on ILC3 innate lymphoid cells and plays a role in their activation and cytokine production. IL-23R+ ILC3s respond to IL-23 signaling by releasing IL-17 and IL-22, which support epithelial barrier integrity and promote tissue remodeling. These cells are involved in defending against extracellular pathogens, particularly in the gut, by coordinating immune responses and maintaining mucosal homeostasis. IL23R expression helps identify functionally active ILC3 subsets in inflammatory and microbial contexts.

Figure 13. Immunocytochemistry/ Immunofluorescence - Anti-IL-23R antibody [EPR22838-4] (ab222104).

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Natural killer (NK) cells are a well-characterized subset of innate lymphoid cells known for their role in immune surveillance and cytotoxic activity. Unlike adaptive immune cells, NK cells respond rapidly to infected or transformed cells without prior sensitization. They are typically identified by markers such as CD56 and CD16, and the absence of CD3, along with expression of transcription factors like Eomes and T-bet.

Recent studies have highlighted the diversity within NK cell populations, including tissue-resident and circulating subsets. These subsets differ in marker expression and functional capacity, contributing to varied inflammation, infection, and cancer responses. Advances in single-cell transcriptomics have revealed new NK cell states and their potential overlap with other ILC1 populations. This evolving understanding is refining how researchers classify innate lymphoid cells and explore their roles in immune regulation and therapeutic development.

CD3

CD3 is a negative control marker distinguishing natural killer cells from T cells within the innate lymphoid cell family. NK cells lack CD3 expression, which helps identify them as non-T lymphocytes. These innate immune system lymphocytes eliminate tumor cells and microbe-infected cells. They produce cytotoxic molecules such as perforin and granzymes and act independently of antigen-specific receptors. The absence of CD3 supports accurate identification of NK cells in studies of immune surveillance and cytotoxic responses.

Figure 14. Flow Cytometry - Anti-CD3 epsilon antibody [EPR5361(2)] (ab133628).

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CD56

CD56 is a surface marker commonly used to identify natural killer cells, a subset of innate lymphoid cells. These lymphocytes are part of the innate immune system and play a role in eliminating tumor cells and microbe-infected cells. CD56+ NK cells produce cytotoxic molecules such as perforin and granzymes, enabling rapid immune responses without prior sensitization. Their activity supports immune surveillance and contributes to early defense mechanisms. CD56 expression helps distinguish NK cells from other lymphocyte populations in immunological studies.

Figure 15. Immunohistochemistry (Formalin/PFA-fixed paraffin-embedded sections) - Anti-NCAM1 antibody [EPR26939-108] (ab313779).

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CD94

CD94 is a surface receptor expressed on natural killer cells, a subset of innate lymphoid cells. It forms heterodimers with NKG2 molecules and contributes to immune recognition of stressed or infected cells. CD94+ NK cells are involved in eliminating tumors and microbe-infected cells by releasing cytotoxic molecules such as perforin and granzymes. These lymphocytes act independently of antigen specificity and respond rapidly to immune challenges. CD94 expression helps identify NK cell subsets and supports studies on cytotoxic responses and immune surveillance.

Figure 16. Flow Cytometry - Anti-CD94 antibody [EPR23229-138] (ab245240).

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CD335

CD335, also known as NKp46 and NCR1, is a surface receptor expressed on natural killer cells, a subset of innate lymphoid cells. It plays a role in recognizing infected or transformed cells and initiating cytotoxic responses. CD335+ NK cells contribute to the elimination of tumors and microbe-infected cells by releasing perforin, granzymes, and inflammatory cytokines. These lymphocytes act independently of antigen specificity and respond rapidly to immune challenges. CD335 expression supports the identification of NK cell subsets involved in immune surveillance and early defense.

Figure 17. Flow Cytometry - Anti-NCR1 antibody [EPR22403-40] (ab244208).

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Lymphoid tissue inducer (LTi) cells are a specialized subset of group 3 innate lymphoid cells (ILC3s) involved in the development of secondary lymphoid organs. These cells are typically identified by the expression of RORγt, CD127, and CD117, along with surface markers such as CCR6 and the absence of NKp46. LTi cells are known for producing lymphotoxin and IL-22, which support lymphoid tissue organization and mucosal barrier function.

LTi cells are most active during embryonic development but can persist into adulthood, particularly in mucosal tissues. Their role extends beyond organogenesis, contributing to immune responses in the gut and other barrier sites. Recent studies have explored how LTi-like cells may influence inflammation and tissue repair, offering insights into their broader immunological functions. Understanding LTi markers and their relationship to other ILC3 subsets is helping researchers refine immune cell classification and investigate new therapeutic strategies.

CD127

CD127, the IL-7 receptor alpha chain, is a marker for lymphoid tissue inducer cells, a subset of innate lymphoid cells. These cells are involved in the formation of secondary lymphoid structures during embryogenesis. CD127+ LTi cells contribute to the development of lymph nodes and Peyer’s patches by interacting with stromal cells and promoting tissue organization. Their activity supports immune system architecture and long-term immune function. CD127 expression helps identify LTi cells in studies of lymphoid organogenesis and mucosal immune development

Figure 18. Flow Cytometry - Anti-CD127 antibody [EPR22835-249] (ab255816).

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CD117

CD117, also known as c-Kit, is a surface receptor expressed on lymphoid tissue inducer cells, a subset of innate lymphoid cells. These cells contribute to the formation of lymph nodes and Peyer’s patches during embryogenesis. CD117+ LTi cells interact with stromal cells and promote the organization of lymphoid structures. Their activity supports the development of immune architecture and long-term immune function. CD117 expression helps identify LTi cells in studies of lymphoid organogenesis and mucosal immune system formation.

Figure 19. Flow Cytometry - Anti-c-Kit antibody [EPR25707-134] (ab283653).

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IL-23R

IL-23R, the interleukin-23 receptor, is expressed on lymphoid tissue inducer cells, a subset of innate lymphoid cells involved in early immune system formation. During embryogenesis, IL-23R+ LTi cells contribute to the development of lymph nodes and Peyer’s patches by interacting with stromal cells and promoting lymphoid tissue organization. These cells help establish immune architecture and support long-term immune function. IL-23R expression is used to identify active LTi populations in studies of lymphoid organogenesis and mucosal immune development.

Figure 20. Immunocytochemistry/ Immunofluorescence - Anti-IL-23R antibody [EPR22838-4] (ab222104).

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References

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2. Chen, Q.  et al.  Delineation of Natural Killer Cell Differentiation from Myeloid Progenitors in Human.  Sci. Rep.  5, (2015).

3. Colucci, F., Caligiuri, M., Di Santo, J.P. What does it take to make a natural killer?  Nat. Rev. Immunol.  3, 413–425 (2003).

4. Montaldo, E.  et al.  Human NK cell receptors/markers: A tool to analyze NK cell development, subsets and function.  Cytom. A  83, 702–713 (2013).

5. Farag, S.S., Caligiuri, M.A. Human natural killer cell development and biology.  Blood Rev.  20, 123–137 (2006).