Groundbreaking studies have designated Signaling Lymphocyte Activation Molecule Family Member 7 (SLAMF7, CD319) as a pivotal surface marker. Mattoo and colleagues were the first to identify the prominent clonal expansion of SLAMF7+ CD4+ T cells within both the peripheral blood and affected tissues of IgG4-RD patients (4). These findings were subsequently validated and expanded upon by independent cohorts (20–22), confirming SLAMF7 as a robust pathogenic signature. This observed oligoclonal expansion strongly implies an antigen-driven proliferation event originating from a limited pool of precursor cells (4, 20, 23). The expression of SLAMF7 shows a robust correlation with cytotoxicity, likely augmenting effector function via homophilic interactions that stabilize cell-to-cell contact (20, 24). Crucially, the concurrent enrichment of the chemokine receptor CX3CR1 and the terminal differentiation marker CD57 endows these SLAMF7+ CD4+ T cells with essential tissue-homing capabilities and characteristics indicative of an advanced effector state (25–28).

Regarding transcriptional regulation, CD4+ CTLs notably deviate from canonical helper subsets: they fail to express the lineage-defining master factors GATA3 (Th2) or Bcl6 (Tfh). Instead, they exhibit high expression of T-bet (TBX21) and Eomesodermin(Eomes), transcription factors intrinsically linked to cellular cytotoxicity and effector function (29, 30). Research indicates that T-bet and Eomes exert overlapping yet complementary roles in the induction of key effector molecules, including perforin, granzymes, and Interferon-γ(IFN-γ) (30, 31). Furthermore, the transcription factor Hobit is implicated in sustaining both the cytotoxic program and the tissue-resident phenotype of these cells (31, 32). This distinct and tightly regulated transcriptional network ultimately constitutes the molecular foundation driving the acquisition and long-term maintenance of the CD4+ CTLs’ lethal killing capacity and pronounced pro-inflammatory phenotype.

CD4+ CTLs in IgG4-RD are recognized as highly potent effector cells. They store and subsequently release classic cytotoxic granule components, including perforin, Granzyme A, and Granzyme B (4, 33, 34). Perforin functions by forming transmembrane channels on target cell membranes, which facilitates the entry of granzymes into the cytosol. Granzymes then directly initiate target cell apoptosis through the cleavage of critical substrates, such as caspases (14, 35).

Of greater pathological significance is the distinct cytokine profile secreted by these cells. Unlike the typical Th2 signature, which primarily features IL-4, IL-5, and IL-13, CD4+ CTLs predominantly generate IFN-γ, IL-1β, and TGF-β1 (4, 36–38). It is this specific molecular convergence that underpins their functional duality, equipping them to wield destructive inflammatory power while concurrently orchestrating the machinery of fibrosis. As a potent pro-inflammatory mediator, IFN-γ activates macrophages, thereby exacerbating the local inflammatory response (39). Conversely, TGF-β1 is widely recognized as one of the most powerful pro-fibrotic factors. It directly activates fibroblasts, promoting their transdifferentiation into myofibroblasts and resulting in the excessive deposition of the Extracellular Matrix (40–42). Moreover, IL-1β further amplifies inflammatory signals and acts synergistically with TGF-β to accelerate the progression of fibrosis (43, 44). Collectively, these data suggest that CD4+ CTLs function as a mobilized fibrotic driver unit, capable of precisely delivering both cellular cytotoxic and pro-fibrotic signals directly into the pathological lesion.

Single-cell RNA sequencing (scRNA-seq) offers robust evidence for the precise identification of CD4+ CTLs within complex tissue microenvironments. Maehara et al. analyzed scRNA-seq data from affected IgG4-RD tissues (pancreas, kidney, salivary glands) (45, 46). This analysis revealed that the most pronounced clonal expansion among tissue-infiltrating T cells belonged to CD4+ T cells characterized by a cytotoxic gene signature (high expression of *Granzyme A*, *Granzyme B*, *PRF1*, *IFNG*, and *SLAMF7*). Collectively, these transcriptomic data confirm that CD4+ CTLs are the dominant and clonally expanded T cell population in IgG4-RD lesions, displacing traditional Th2 or other helper subsets.

T-cell receptor (TCR) sequencing analyses have demonstrated that CD4+ CTLs infiltrating affected tissues possess a highly restricted TCR repertoire, where a limited number of clones achieve clonal dominance (4, 47). This phenomenon suggests that specific peptide-MHC Class II complexes may persistently activate corresponding naïve or memory CD4+ T cells, thereby driving their selective expansion and subsequent differentiation into a cytotoxic effector phenotype.

Although the specific antigens driving IgG4-RD remain unidentified, the “chronic, repetitive antigenic stimulation” model constitutes the central mechanistic hypothesis explaining the genesis of CD4+ CTLs. Potential sources for these antigens include microbial agents (such as viruses), autoantigens, and neoantigens exposed following tissue injury.

Given the critical role of CD4+ CTLs in controlling latent infections such as Epstein-Barr virus and Cytomegalovirus, researchers have hypothesized that the reactivation or persistent antigenic exposure from these viruses may serve as a potential trigger for IgG4-RD (10).

Studies confirm that primary Epstein-Barr virus infection induces robust, antigen-specific CD4+ CTL responses (48, 49). In the context of chronic infection, sustained antigenic stimulation is known to propel CD4+ T cells toward a terminally differentiated cytotoxic phenotype (48, 50). However, it is crucial to acknowledge that direct evidence establishing a causal link between specific viral infections and IgG4-RD remains elusive. While the “hit-and-run” hypothesis or persistent viral antigen exposure is biologically plausible, no specific viral genome has been consistently isolated from IgG4-RD lesions across studies. Thus, the viral etiology currently serves as a theoretical framework rather than a proven mechanism.

A distinct cytokine milieu is indispensable for the differentiation of CD4+ T cells into the CTL phenotype. Cytokines such as IL-2, IL-12, and IL-15 strongly promote the expression of the crucial transcription factors T-bet and Eomes, concomitantly upregulating the production of key cytotoxic molecules like granzyme and perforin (51–54).

Furthermore, given that IL-21 has been demonstrated to enhance the cytotoxic function of CD8+ T cells, its potential role in the differentiation pathway of CD4+ CTLs warrants focused investigation (55, 56). Although direct evidence of IL-21 driving CD4+ CTL differentiation specifically within IgG4-RD tissues is still emerging, generally elevated IL-21 levels in IgG4-RD (typically associated with Tfh cells) could theoretically contribute to this process. In the inflammatory microenvironment characteristic of IgG4-RD, these cytokines—secreted by infiltrating plasma cells, B cells, and macrophages—likely synergize to form a unique “cytokine cocktail” that specifically drives the differentiation of naïve or central memory CD4+ T cells into CD4+ CTLs (57–59).

CD4+ CTLs primarily execute target cell lysis through two canonical pathways: the perforin-granzyme pathway and the Fas Ligand(FasL)-Fas pathway. Target cells typically express MHC Class II molecules. In affected tissues, such as salivary glands, pancreatic ducts, and bile ducts, inflammatory stimuli induce the upregulation of MHC Class II on epithelial and endothelial cells, converting these cells into key targets for CD4+ CTL attack (60–62). The release of perforin and Granzyme B directly triggers programmed cell death (apoptosis) in the target cells (35, 63). Concurrently, the interaction between FasL expressed on CD4+ CTLs and Fas on the target cell surface activates the canonical death receptor-mediated apoptotic cascade (52, 64). Of note, environmental factors such as oxidative stress can significantly enhance the susceptibility of endothelial cells to Fas-mediated apoptosis (64, 65).

This direct cellular killing is the initiating event for ensuing tissue injury and structural disruption. Apoptotic cells subsequently release abundant intracellular antigens and damage-associated molecular pattern (66), thereby amplifying the localized inflammatory cycle and providing the requisite initiating signals for subsequent tissue remodeling and fibrosis (67).

The induction of fibrosis stands out as one of the most critical and high-impact pathogenic contributions of CD4+ CTLs to the immunopathology of IgG4-RD. Their pro-fibrotic effects are mediated both through soluble cytokines (68) and via direct, apoptosis-independent mechanisms (69).

Cytokine-mediated fibrosis centers on TGF-β1 secreted by CD4+ CTLs, which critically drives fibroblast activation and subsequent Extracellular Matrix synthesis (40). This effect is amplified by IL-1β, which acts synergistically with TGF-β to potentiate pro-fibrotic gene expression. Crucially, these CD4+ CTLs concurrently release IFN-γ, a factor largely deemed anti-fibrotic due to its capacity to suppress TGF-β signaling and fibroblast collagen synthesis (40, 70, 71). Therefore, IgG4-RD-associated fibrosis evolves within a complex microenvironment defined by this imbalance between pro- and anti-fibrotic factors; yet, the robust pro-fibrotic signaling provided by the CD4+ CTLs ultimately prevails.

Recent studies have demonstrated that Granzyme A possesses an apoptosis-independent profibrotic function. Extracellular Granzyme A cleaves crucial Extracellular Matrix components, such as Type IV collagen and fibronectin, thereby compromising basement membrane integrity (72, 73). Crucially, Granzyme A directly activates fibroblasts by proteolytically cleaving and activating protease-activated receptor-1 (PAR-1) (74, 75). PAR-1 activation, a G protein-coupled receptor signaling event, subsequently initiates intracellular calcium mobilization, RhoA activation, and the MAPK signaling cascade. These downstream events culminate in heightened fibroblast proliferation, migration, and augmented collagen synthesis (75, 76). This mechanism effectively couples the cytotoxic effector functions of CD4+ CTLs with their capacity for tissue remodeling, allowing for a devastating “dual-mode” progression of the disease.

While CD4+ CTLs provide a robust explanation for the intensity of fibrosis via TGF-β1, IL-1β, and Granzyme A-mediated matrix remodeling, the mechanism driving the specific “storiform” (cartwheel-like) architectural pattern remains an intriguing open question. The storiform pattern likely results from complex spatial interactions between activated myofibroblasts, inflammatory cells, and the physical forces within the edematous tissue, rather than cytokine signaling alone. Whether CD4+ CTLs influence this spatial arrangement through specific cell-cell contact or localized matrix cleavage requires further high-resolution spatial transcriptomic analysis.

A critical and intricate interplay exists between CD4+ CTLs and the B cell/plasma cell lineage, establishing a central axis in IgG4-RD immunopathology.

While some observations note low-level expression of Bcl6 or CXCR5 on CD4+ CTLs, hinting at a potential Tfh-like function (77), the prevailing consensus classifies this population as a distinct subset. Its defining characteristic remains cytotoxicity rather than canonical T-helper activity (77, 78). Consequently, these cells may not directly dictate IgG4 class switching but instead modulate B cell activation and differentiation indirectly by orchestrating a specific inflammatory milieu.

A widely accepted model posits that activated B cells and plasma cells function as highly efficient antigen-presenting cells (APCs), sustaining the activation and clonal expansion of CD4+ CTLs through continuous antigen presentation via MHC Class II molecules (10, 50, 79, 80). This interaction establishes a potent positive feedback loop: activated CD4+ CTLs drive inflammation and subsequent tissue damage, which, in turn, releases a greater antigenic burden. B cells subsequently internalize, process, and present these liberated antigens, thereby perpetuating the stimulation of the CD4+ T cell population. Crucially, this mechanism elegantly accounts for the pronounced therapeutic efficacy of the B-cell-depleting agent Rituximab. Rituximab achieves clinical remission by not only eliminating antibody-producing cells, but also by interrupting this T-B cell axis, which leads to a concomitant decline in CD4+ CTL populations (59, 81–84).