综述：第3组先天淋巴细胞的抗原呈递能力：对T细胞免疫效应或耐受效应的启示

《European Journal of Immunology》：The Antigen Presenting Capabilities of Group 3 Innate Lymphoid Cells: Insights Into Immunogenic or Tolerogenic Outcomes for T Cells

ILC3s通过MHC II介导抗原呈递，在免疫调节中发挥双重作用：抑制效应性T细胞并促进调节性T细胞分化，同时在外部刺激下成熟增强抗原呈递能力激活T细胞，影响肠道、淋巴结及中枢神经系统的免疫应答和疾病进程。

　　
Group 3 innate lymphoid cells (ILC3s) represent a specialized subset of innate lymphocytes that play dual roles in immune regulation, balancing tolerance and activation. As tissue-resident lymphocytes distributed across both lymphoid and non-lymphoid tissues, ILC3s are characterized by the transcription factor RORγt and can rapidly respond to environmental cues. This review explores their mechanisms of antigen presentation, tissue-specific behaviors, and implications for immune homeostasis and diseases.

### Core Functions and Molecular Basis
ILC3s are defined by RORγt expression, which drives their capacity to secrete cytokines like IL-17 and GM-CSF critical for mucosal defense. A key discovery is the existence of a subset of MHCII+ ILC3s, particularly in lymphoid tissues and mucosal sites. These cells utilize CIITA, a transcriptional activator similar to thymic epithelial cells (TECs), to upregulate MHCII expression. This process is tissue-specific: splenic ILC3s activate the CIITA pIV promoter under IFN-γ exposure, while intestinal counterparts primarily rely on the pI promoter. Notably, extrathymic AIRE-expressing ILC3s (eTACs) in mice share regulatory pathways with TECs, though they lack IL-7Rα and are enriched in peripheral lymph nodes rather than mucosa.

### Antigen Presentation and T Cell Modulation
The MHCII+ ILC3 subset directly presents antigens to CD4+ T cells, a capability regulated by CIITA. This function is dynamic and context-dependent. In the small intestine, LTi-like ILC3s (CCR6+ NKp46–) present antigens through MHCII and costimulatory molecules, yet their APC capacity is suppressed by gut microbiota and IL-23. This suppression is reversible upon migration to lymph nodes, where IL-1β and IFN-γ trigger maturation—upregulating costimulatory molecules (OX40L, CD40) and enhancing antigen-presenting efficiency. In contrast, splenic ILC3s respond to IFN-γ by activating CIITA pIV, fully maturing into APCs that promote Th17 and Tfh responses.

### Tissue-Specific Plasticity and Migration
ILC3s exhibit remarkable plasticity based on tissue microenvironments. Intestinal ILC3s maintain tolerogenic functions by restricting T cell activation and promoting regulatory T cell (Treg) differentiation. Their antigen presentation relies on low-costimulatory expression, leading to T cell apoptosis rather than proliferation. Conversely, splenic ILC3s migrate to lymphoid structures under inflammatory stimuli, acquiring robust APC capabilities. Human studies reveal three ILC3 subsets: NKp44+ (corresponding to murine NCR+ ILC3s), HLA class II+ (analogous to LTi-like cells), and SELL+ naive precursors. Migration mechanisms, such as CCR7mediated lymph node trafficking, are critical for ILC3s to adapt to local immune demands.

### Dual Role in Immune Homeostasis and Disease
The dual functionality of ILC3s—tolerance versus activation—depends on environmental cytokines. Under normal conditions, intestinal ILC3s suppress effector T cells via MHCII presentation and secrete IL-22 to maintain barrier integrity. However, during infections or inflammation, cytokines like IL-1β trigger maturation, enabling ILC3s to activate pathogenic T cells. This switch has been observed in autoimmune encephalomyelitis (EAE), where CNS-derived ILC3s promote neuroinflammation by presenting myelin antigens to CD4+ T cells. Similarly, in colorectal cancer (CRC), MHCII+ ILC3s enhance Th1 responses and tertiary lymphoid structure formation, improving anti-PD-1 therapy efficacy.

### Mechanisms of Antigen Uptake and Presentation
ILC3s possess intrinsic antigen uptake capabilities, demonstrated through phagocytosis of latex beads and processing of ovalbumin/OVA in mice. Human studies confirm that HLA-DR+ ILC3-like cells internalize and degrade antigens, enabling cross-presentation. However, intestinal ILC3s are less efficient at T cell activation compared to splenic counterparts, attributed to suppressed MHCII and costimulatory molecule expression. This difference is regulated by local factors: gut microbiota inhibit MHCII via mTORC1/STAT3 pathways, while splenic ILC3s respond to IFN-γ by upregulating CIITA and co-stimulatory molecules.

### Clinical Implications and Therapeutic Potential
The ability of ILC3s to toggle between tolerance and activation positions them as therapeutic targets. In cancer, enhancing ILC3 APC activity through IL-1β or IFN-γ stimulation promotes anti-tumor T cell responses. In inflammatory bowel disease (IBD), modulating ILC3 plasticity could restore mucosal tolerance. Autoimmune diseases like EAE show that CNS ILC3s drive pathogenic T cells via MHCII presentation, suggesting targeted depletion or differentiation could alleviate symptoms. Current research focuses on dissecting tissue-specific regulatory networks and identifying biomarkers for clinical manipulation.

### Future Directions
Key research gaps include understanding the full spectrum of RORγt+ APCs (e.g., eTACs, DC-like subsets) and mechanisms governing ILC3 recruitment under inflammation. Comparative studies across tissues (intestine, lung, CNS) are needed to clarify how local cues shape ILC3 identity. Additionally, exploring the role of ILC3s in cancer metastasis and their interplay with tumor microenvironments could unlock novel therapeutic strategies. Advances in single-cell omics and organoid models will be critical for disentangling ILC3 subpopulations and their functional consequences.

### Summary
ILC3s exemplify how innate lymphocytes integrate tissue-specific signals to fulfill dual roles in immune regulation. Their capacity to present antigens via MHCII, modulated by CIITA and environmental cytokines, enables them to either suppress T cell responses or promote adaptive immunity. This plasticity underpins their importance in maintaining mucosal tolerance while contributing to pathological processes like autoimmunity and cancer. Future studies must address tissue specificity, lineage dynamics, and therapeutic targeting to fully harness ILC3 potential in health and disease.