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Effective and sustained inhibition of non-enzymatic oncogenic driver proteins is a major pharmacological challenge. The clinical success of thalidomide analogues demonstrates the therapeutic efficacy of drug-induced degradation of transcription factors and other cancer targets 1 – 3 , but a substantial subset of proteins are resistant to targeted degradation using existing approaches 4 , 5 . Here we report an alternative mechanism of targeted protein degradation, in which a small molecule induces the highly specific, reversible polymerization of a target protein, followed by its sequestration into cellular foci and subsequent degradation. BI-3802 is a small molecule that binds to the Broad-complex, Tramtrack and Bric-à-brac (BTB) domain of the oncogenic transcription factor B cell lymphoma 6 (BCL6) and leads to the proteasomal degradation of BCL6 6 . We use cryo-electron microscopy to reveal how the solvent-exposed moiety of a BCL6-binding molecule contributes to a composite ligand–protein surface that engages BCL6 homodimers to form a supramolecular structure. Drug-induced formation of BCL6 filaments facilitates ubiquitination by the SIAH1 E3 ubiquitin ligase. Our findings demonstrate that a small molecule such as BI-3802 can induce polymerization coupled to highly specific protein degradation, which in the case of BCL6 leads to increased pharmacological activity compared to the effects induced by other BCL6 inhibitors. These findings open new avenues for the development of therapeutic agents and synthetic biology. Binding of the small molecule BI-3802 to the oncogenic transcription factor B cell lymphoma 6 (BCL6) induces polymerization of BCL6, leading to its ubiquitination by SIAH1 and proteasomal degradation.

Memory B cells (MBCs) are essential for long-lived humoral immunity. However, the transcription factors involved in MBC differentiation are poorly defined. Here, using single-cell RNA sequencing analysis, we identified a population of germinal center (GC) B cells in the process of differentiating into MBCs. Using an inducible CRISPR–Cas9 screening approach, we identified the hematopoietically expressed homeobox protein Hhex as a transcription factor regulating MBC differentiation. The corepressor Tle3 was also identified in the screen and was found to interact with Hhex to promote MBC development. Bcl-6 directly repressed Hhex in GC B cells. Reciprocally, Hhex-deficient MBCs exhibited increased Bcl6 expression and reduced expression of the Bcl-6 target gene Bcl2 . Overexpression of Bcl-2 was able to rescue MBC differentiation in Hhex-deficient cells. We also identified Ski as an Hhex-induced transcription factor involved in MBC differentiation. These findings establish an important role for Hhex–Tle3 in regulating the transcriptional circuitry governing MBC differentiation. Generation of memory B cells is crucial for protective immunity to infectious agents. Cyster and colleagues show that the transcription factor Hhex interacting with Tle3 promotes memory B cell generation.

B cells and follicular helper T cells in B cell follicles can act as important reservoirs for chronic infection by viruses such as HIV or EBV. Yu and colleagues show that a specialized subpopulation of cytotoxic T cells can enter the B cell follicles to eliminate such virus-infected cells. During unresolved infections, some viruses escape immunological control and establish a persistant reservoir in certain cell types, such as human immunodeficiency virus (HIV), which persists in follicular helper T cells (T FH cells), and Epstein-Barr virus (EBV), which persists in B cells. Here we identified a specialized group of cytotoxic T cells (T C cells) that expressed the chemokine receptor CXCR5, selectively entered B cell follicles and eradicated infected T FH cells and B cells. The differentiation of these cells, which we have called 'follicular cytotoxic T cells' (T FC cells), required the transcription factors Bcl6, E2A and TCF-1 but was inhibited by the transcriptional regulators Blimp1, Id2 and Id3. Blimp1 and E2A directly regulated Cxcr5 expression and, together with Bcl6 and TCF-1, formed a transcriptional circuit that guided T FC cell development. The identification of T FC cells has far-reaching implications for the development of strategies to control infections that target B cells and T FH cells and to treat B cell–derived malignancies.

Genes that drive the proliferation, survival, invasion and metastasis of malignant cells have been identified for many human cancers 1 – 4 . Independent studies have identified cell death pathways that eliminate cells for the good of the organism 5 , 6 . The coexistence of cell death pathways with driver mutations suggests that the cancer driver could be rewired to activate cell death using chemical inducers of proximity (CIPs). Here we describe a new class of molecules called transcriptional/epigenetic CIPs (TCIPs) that recruit the endogenous cancer driver, or a downstream transcription factor, to the promoters of cell death genes, thereby activating their expression. We focused on diffuse large B cell lymphoma, in which the transcription factor B cell lymphoma 6 (BCL6) is deregulated 7 . BCL6 binds to the promoters of cell death genes and epigenetically suppresses their expression 8 . We produced TCIPs by covalently linking small molecules that bind BCL6 to those that bind to transcriptional activators that contribute to the oncogenic program, such as BRD4. The most potent molecule, TCIP1, increases binding of BRD4 by 50% over genomic BCL6-binding sites to produce transcriptional elongation at pro-apoptotic target genes within 15 min, while reducing binding of BRD4 over enhancers by only 10%, reflecting a gain-of-function mechanism. TCIP1 kills diffuse large B cell lymphoma cell lines, including chemotherapy-resistant, TP53 -mutant lines, at EC 50 of 1–10 nM in 72 h and exhibits cell-specific and tissue-specific effects, capturing the combinatorial specificity inherent to transcription. The TCIP concept also has therapeutic applications in regulating the expression of genes for regenerative medicine and developmental disorders. A new class of molecules can recruit downstream transcription factors or endogenous cancer drivers to cell death promoters and activate the expression of these genes.

T follicular helper (T FH ) cells are a distinct type of CD4 + T cells that are essential for most antibody and B lymphocyte responses. T FH cell regulation and dysregulation is involved in a range of diseases. Bcl-6 is the lineage-defining transcription factor of T FH cells and its activity is essential for T FH cell differentiation and function. However, how Bcl-6 controls T FH biology has largely remained unclear, at least in part due to the intrinsic challenges of connecting repressors to gene upregulation in complex cell types with multiple possible differentiation fates. Multiple competing models were tested here by a series of experimental approaches to determine that Bcl-6 exhibits negative autoregulation and controls pleiotropic attributes of T FH differentiation and function, including migration, costimulation, inhibitory receptors and cytokines, via multiple repressor-of-repressor gene circuits. Bcl-6 is the signature transcription factor for T FH cells. Crotty and colleagues provide a comprehensive transcriptional map depicting the regulatory circuitry controlled by Bcl-6 in determining T FH cell fate and function.

Humoral immunity is necessary for controlling viral infection. Ballesteros-Tato and colleagues show that development of follicular regulatory T cells is prevented by high concentrations of interleukin 2 at the peak of viral infection, but resumes at later time points to suppress autoantibody production. Interleukin 2 (IL-2) promotes Foxp3 + regulatory T (T reg ) cell responses, but inhibits T follicular helper (T FH ) cell development. However, it is not clear how IL-2 affects T follicular regulatory (T FR ) cells, a cell type with properties of both T reg and T FH cells. Using an influenza infection model, we found that high IL-2 concentrations at the peak of the infection prevented T FR cell development by a Blimp-1-dependent mechanism. However, once the immune response resolved, some T reg cells downregulated CD25, upregulated Bcl-6 and differentiated into T FR cells, which then migrated into the B cell follicles to prevent the expansion of self-reactive B cell clones. Thus, unlike its effects on conventional T reg cells, IL-2 inhibits T FR cell responses.

Immunoglobulin E (IgE) is a type of antibody associated with allergies and response to parasites such as worms. When high-affinity, allergen-specific IgE binds its target, it can cross-link receptors on mast cells that induce anaphylaxis. It remains unclear, however, how B cells are instructed to generate high-affinity IgE. Gowthaman et al. discovered a subset of T follicular helper cells (T FH 13) that direct B cells to do just that. T FH 13 cells are induced by allergens but not during parasite infection. Transgenic mice lacking these cells show impaired production of high-affinity, anaphylactic IgE. T FH 13 cells, which are elevated in patients with food and aeroallergies, may be targeted in future antianaphylaxis therapies. Science , this issue p. eaaw6433 So-called T FH 13 cells promote the production of high-affinity immunoglobulin E involved in allergic anaphylaxis. Cross-linking of high-affinity immunoglobulin E (IgE) results in the life-threatening allergic reaction anaphylaxis. Yet the cellular mechanisms that induce B cells to produce IgE in response to allergens remain poorly understood. T follicular helper (T FH ) cells direct the affinity and isotype of antibodies produced by B cells. Although T FH cell–derived interleukin-4 (IL-4) is necessary for IgE production, it is not sufficient. We report a rare population of IL-13–producing T FH cells present in mice and humans with IgE to allergens, but not when allergen-specific IgE was absent or only low-affinity. These “T FH 13” cells have an unusual cytokine profile (IL-13 hi IL-4 hi IL-5 hi IL-21 lo ) and coexpress the transcription factors BCL6 and GATA3. T FH 13 cells are required for production of high- but not low-affinity IgE and subsequent allergen-induced anaphylaxis. Blocking T FH 13 cells may represent an alternative therapeutic target to ameliorate anaphylaxis.

Oncolytic viruses (OVs) emerge as a promising cancer immunotherapy. However, the temporal impact on tumor cells and the tumor microenvironment, and the nature of anti-tumor immunity post-therapy remain largely unclear. Here we report that CD4 + T cells are required for durable tumor control in syngeneic murine models of glioblastoma multiforme after treatment with an oncolytic herpes simplex virus (oHSV) engineered to express IL-12. The upregulated MHCII on residual tumor cells facilitates programmed polyfunctional CD4 + T cells for tumor control and for recall responses. Mechanistically, the proper ratio of Bcl-6 to T-bet in CD4 + T cells navigates their enhanced anti-tumor capacity, and a reciprocal IL6ra-Bcl-6 regulatory axis in a memory CD4 + T-cell subset, which requires MHCII signals from reprogrammed tumor cells, tumor-infiltrating and resident myeloid cells, is necessary for the prolonged response. These findings uncover an OV-induced tumor/myeloid-CD4 + T-cell partnership, leading to long-term anti-tumor immune memory, and improved OV therapeutic efficacy. Oncolytic herpes simplex virus−1 (oHSV) can boost anti-tumor immune responses in gliomas. Here the authors report that CD4 + T cells are required for the therapeutic activity of an oHSV-engineered to express IL-12 in preclinical glioblastoma models.

The authors identify in patients with rheumatoid arthritis a pathogenic subset of CD4+ T cells that augments B cell responses within inflamed tissues. Peripheral helper T cells in rheumatoid arthritis Michael Brenner and colleagues identify a subset of pathogenically activated PD-1 hi CD4-positive T cells in patients with rheumatoid arthritis, and show that it promotes B-cell responses in tertiary lymphoid structures. The cells, which the authors designate as 'peripheral helper' T cells, differ from follicular helper cells in that they lack CXCR5, have altered BCL6 expression, and express chemokine receptors that direct migration to inflamed sites. CD4 + T cells are central mediators of autoimmune pathology; however, defining their key effector functions in specific autoimmune diseases remains challenging. Pathogenic CD4 + T cells within affected tissues may be identified by expression of markers of recent activation 1 . Here we use mass cytometry to analyse activated T cells in joint tissue from patients with rheumatoid arthritis, a chronic immune-mediated arthritis that affects up to 1% of the population 2 . This approach revealed a markedly expanded population of PD-1 hi CXCR5 − CD4 + T cells in synovium of patients with rheumatoid arthritis. However, these cells are not exhausted, despite high PD-1 expression. Rather, using multidimensional cytometry, transcriptomics, and functional assays, we define a population of PD-1 hi CXCR5 − ‘peripheral helper’ T (T PH ) cells that express factors enabling B-cell help, including IL-21, CXCL13, ICOS, and MAF. Like PD-1 hi CXCR5 + T follicular helper cells, T PH cells induce plasma cell differentiation in vitro through IL-21 secretion and SLAMF5 interaction (refs 3 , 4 ). However, global transcriptomics highlight differences between T PH cells and T follicular helper cells, including altered expression of BCL6 and BLIMP1 and unique expression of chemokine receptors that direct migration to inflamed sites, such as CCR2, CX3CR1, and CCR5, in T PH cells. T PH cells appear to be uniquely poised to promote B-cell responses and antibody production within pathologically inflamed non-lymphoid tissues.

The transcription factor BATF is known to control switched antibody responses. Murphy and colleagues show that BATF functions at multiple hierarchical levels in follicular helper T cells and B cells to regulate these responses. The transcription factor BATF controls the differentiation of interleukin 17 (IL-17)-producing helper T cells (T H 17 cells) by regulating expression of the transcription factor RORγt itself and RORγt target genes such as Il17 . Here we report the mechanism by which BATF controls in vivo class-switch recombination (CSR). In T cells, BATF directly controlled expression of the transcription factors Bcl-6 and c-Maf, both of which are needed for development of follicular helper T cells (T FH cells). Restoring T FH cell activity to Batf −/− T cells in vivo required coexpression of Bcl-6 and c-Maf. In B cells, BATF directly controlled the expression of both activation-induced cytidine deaminase (AID) and of germline transcripts of the intervening heavy-chain region and constant heavy-chain region (I H -C H ). Thus, BATF functions at multiple hierarchical levels in two cell types to globally regulate switched antibody responses in vivo .