ILC2s ride the Blimp to fly

Our understanding of the ways in which immune cell phenotypes and functions are regulated is constantly changing, no more so than for group 2 innate lymphoid cells (ILC2s), an innate immune cell type that is integral to the type 2 immune response that drives protection against parasitic worm infection and promotes tissue repair but can also drive allergic inflammation.

ILC2s operate at the onset of immune responses and are believed to be uniquely positioned to respond rapidly as effector cells following activation via local tissue danger signals known as alarmins. In contrast to the adaptive immune system, tissue-resident ILC2s have classically been considered to be transcriptionally poised effector cells, with the majority of their effector capacity imprinted by master transcription factors during development (Shih et al., 2016). While activating cues—including alarmins—can potently induce ILC2 proliferation and cytokine production, the degree to which these cues further augment the ILC2 transcriptional program to enable robust effector function has remained unclear. Here, Forster et al. (2026) identify Blimp-1 as an alarmin-triggered transcription factor that is critical to license optimal ILC2 effector cytokine secretion (see figure).

Using knockout mice deficient in alarmin-related genes, including the IL-33 receptor (IL-33R), IL-25R, and TSLPR, the authors identified discrete gene signatures associated with the presence or absence of individual alarmins, both at steady state and in the context of helminth infection. At steady state, individual alarmins were found to be associated with specific transcriptional changes, suggesting these cues may differentially effect aspects of ILC2 biology, including cytokine production, proliferation, cell migration, and cellular cross talk via Notch-dependent pathways.

The alarmin IL-33 was found to induce the highest degree of effector cytokine responses in ILC2 and was associated with canonical modules of signaling associated with cellular activation and proliferation, such as Myc and NK_KB-related genes. Notably, IL-33 was also found to regulate several transcription factor genes—including Prdm1 (encoding Blimp1). Notably, Blimp1 was found to be significantly induced by IL-33 in vitro and in vivo at both the transcriptional and protein level, suggesting this alarmin may further remodel the ILC2 transcriptional landscape through the induction of auxiliary transcription factors.

These findings suggest tonic steady-state levels of IL-33, IL-25, and TSLP may shape aspects of the ILC2 transcriptional program in potentially unique and nonredundant manners. In contrast, following helminth infection, the specificity of alarmin-associated gene modules—including Prdm1—was lost, and transcriptional changes associated with each alarmin overlapped considerably. The reasons for this remain unclear but may reflect the consequence of an individual cell having experienced multiple alarmin cues either consecutively or concurrently or a convergence of signaling pathways that renders further activating cues redundant. Moreover, ILC2s are additionally equipped with a wide array of receptors for bioactive molecules such as nutrients, microbial metabolites, and neuropeptides, provoking the question as to whether these further cues may also play nuanced roles in shaping the biology of ILC2s.

To test the role of Blimp1 in ILC2 function in vivo, the authors generated conditional knockouts of Prdm1 in ILC2. Blimp1 was found to be dispensable for ILC2 development and steady-state phenotype, further suggesting this transcription factor may largely mediate its functions following cell activation, e.g., by IL-33. To explore this further, mice were infected with the helminth Nippostrongylus brasiliensis to determine the consequences of ILC2-intrinsic Blimp1 deficiency following in vivo activation. Strikingly, total ILC2 numbers expanded significantly more in the absence of Prdm1. Careful phenotyping of these cells revealed this was in part due to a preferential expansion of ILC2s exhibiting an “inflammatory” phenotype (inflammatory ILC2 [iILC2]), with a reciprocal decrease in numbers expressing the IL-33R in the lung and intestinal draining lymph node. While total ILC2 numbers were increased in the absence of Blimp1, the authors found their cytokine-producing capacity to be impaired, resulting in reduced eosinophilia and delayed control of worm infection. Single-cell RNA sequencing of Blimp1-deficient ILC2s revealed an increase in proliferative programs at the expense of cytokine-producing capacity. The induction of an iILC2 phenotype has classically been associated with IL-25, which drives proliferation and migration of these cells from the gut to peripheral tissues such as the lung (Huang et al., 2015; Huang et al., 2018; Campbell et al., 2019), while in contrast IL-33 is thought to act via ST2⁺ “natural” ILC2 to favor local cytokine production. These findings suggest Blimp1 may act as a transcriptional rheostat of differential alarmin programing (see figure). Alternatively, Blimp1 activity may be restricted to nILC2s, and thus the absence of Blimp-1 facilitates the dominance of concurrently elicited iILC2s.

Blimp1 deficiency in ILC2s was further associated with reduced IRF4, a transcription factor that acts downstream of Blimp1 and which was similarly dependent upon IL-33 for its induction. Loss of IRF4 impacted the type 2 identity of ILC2 dramatically altering the cytokine and cytokine receptor repertoire of these cells. This included Il9r, which in line with previous findings is required for autocrine feedback that supports survival and effector responses in ILC2s (Mohapatra et al., 2016; Turner et al., 2013). Intriguingly, IRF-deficient ILC2 upregulated type 3 effector cytokine function—something that has previously been associated with iILC2 phenotype (Huang et al., 2015), further suggesting this transcriptional axis may determine the balance between iILC2s and nILC2s intrinsically.

Blimp1 and IRF4 represent transcriptional modules that have been associated with terminally differentiated effector functions in a number of immune cells, including Th2 cells (He et al., 2020), regulatory T cells (Cretney et al., 2011), and natural killer cells (Kallies et al., 2011). These transcription factors are particularly important in the differentiation of antibody-producing plasma cells (Tellier and Nutt, 2019), where they form a broader regulatory network that involves another transcription factor Xbp1, which has also recently been shown to support optimal ILC2 responses (Cui et al., 2026). Xbp1 acts to regulate the unfolded protein response and ER stress, and thus it is possible that the shared transcriptional axis of Blimp1-IRF4-Xbp1 acts across cell types to support the survival of cells that are primed for elevated secretion of their respective immune effector. Blimp1 also interacts with the transcription factor c-maf in a number of cell types to support IL-10, which has previously been demonstrated for ILC2 (Howard et al., 2021), and in concert, these transcription factors act to increase metabolic activity to fuel the energetic demand associated with effector function. Moreover, IRF-4 expression is determined by BACH2 in ILC2s—another transcription factor required for optimal cytokine production (Liu et al., 2025). Thus, these findings position Blimp1 and IRF4 as components of a wider transcriptional network in ILC2s that act as a transcriptional determinant of cytokine secretory capacity.

Over the past decades, ILC biology has often been viewed through the lens of master transcription factor programs that are required during development and to imprint core functions and phenotype. However, prior work across the wider ILC family suggests more complex transcriptional landscapes within these cells. For example, group 3 ILCs utilize co-expression of T-bet to gain pro-inflammatory functions (Klose et al., 2013) or Bcl6 to facilitate cross talk with humoral immunity (Tachó-Piñot et al., 2023). This latest study suggests that similarly ILC2s may utilize auxiliary transcriptional programs induced in the periphery to shape and augment the nature of the ILC response. Finally, the conserved nature of transcriptional modules across effector lymphocyte families highlights the need for a holistic reframing of how transcriptional regulation is viewed in immune cells, with a renewed focus on biological function rather than a historically biased perspective of “cell type–specific” networks.