Lrig1-expression confers suppressive function to CD4+ cells and is essential for averting autoimmunity via the Smad2/3/Foxp3 axis.
2023; 14 (1): 5382
Regulatory T cells (Treg) are CD4+ T cells with immune-suppressive function, which is defined by Foxp3 expression. However, the molecular determinants defining the suppressive population of T cells have yet to be discovered. Here we report that the cell surface protein Lrig1 is enriched in suppressive T cells and controls their suppressive behaviors. Within CD4+ T cells, Treg cells express the highest levels of Lrig1, and the expression level is further increasing with activation. The Lrig1+ subpopulation from T helper (Th) 17 cells showed higher suppressive activity than the Lrig1- subpopulation. Lrig1-deficiency impairs the suppressive function of Treg cells, while Lrig1-deficient naïve T cells normally differentiate into other T cell subsets. Adoptive transfer of CD4+Lrig1+ T cells alleviates autoimmune symptoms in colitis and lupus nephritis mouse models. A monoclonal anti-Lrig1 antibody significantly improves the symptoms of experimental autoimmune encephalomyelitis. In conclusion, Lrig1 is an important regulator of suppressive T cell function and an exploitable target for treating autoimmune conditions.
View details for DOI 10.1038/s41467-023-40986-4
View details for PubMedID 37666819
View details for PubMedCentralID 7882196
Anti-citrullinated protein antibodies with multiple specificities ameliorate collagen antibody-induced arthritis in a time-dependent manner.
Arthritis & rheumatology (Hoboken, N.J.)
Anti-citrullinated protein antibodies (ACPAs) are highly specific for rheumatoid arthritis (RA) and have long been regarded as pathogenic. Despite substantial in vitro evidence supporting this claim, reports investigating the pro-inflammatory effects of ACPAs in animal models of arthritis are rare and include mixed results. Here, we sequenced the plasmablast antibody repertoire of a RA patient and functionally characterized the encoded ACPAs.We expressed ACPAs from the antibody repertoire of a RA patient and characterized their autoantigen specificities on antigen arrays and ELISAs. Binding affinities were estimated by bio-layer interferometry. Select ACPAs (n=9) were tested in the collagen-antibody induced arthritis (CAIA) mouse model, to evaluate their effects on joint inflammation.Recombinant ACPAs bound preferentially, and with high affinity (nM range), to citrullinated (cit) autoantigens (primarily histones and fibrinogen), and to auto-citrullinated peptidylarginine deiminase 4 (PAD4). ACPAs were grouped for in vivo testing based on their predominant cit-antigen specificities. Unexpectedly, injections of recombinant ACPAs significantly reduced paw thickness and arthritis severity in CAIA mice, as compared to isotype-matched control antibodies (p≤0.001). Bone erosion, synovitis, and cartilage damage were also significantly reduced (p≤0.01). This amelioration of CAIA was observed for all the ACPAs tested and was independent of cit-PAD4 and cit-fibrinogen specificities. Further, disease amelioration was more prominent when ACPAs were injected at earlier stages of CAIA than at later phases of the model.Recombinant, patient-derived ACPAs ameliorated CAIA. Their anti-inflammatory effects were more preventative than therapeutic. This study highlights a potential protective role for ACPAs in arthritis.
View details for DOI 10.1002/art.42679
View details for PubMedID 37610274
Cytotoxic CD8+ T cells target citrullinated antigens in rheumatoid arthritis.
2023; 14 (1): 319
The immune mechanisms that mediate synovitis and joint destruction in rheumatoid arthritis (RA) remain poorly defined. Although increased levels of CD8+ T cells have been described in RA, their function in pathogenesis remains unclear. Here we perform single cell transcriptome and T cell receptor (TCR) sequencing of CD8+ T cells derived from anti-citrullinated protein antibodies (ACPA)+ RA blood. We identify GZMB+CD8+ subpopulations containing large clonal lineage expansions that express cytotoxic and tissue homing transcriptional programs, while a GZMK+CD8+ memory subpopulation comprises smaller clonal expansions that express effector T cell transcriptional programs. We demonstrate RA citrullinated autoantigens presented by MHC class I activate RA blood-derived GZMB+CD8+ T cells to expand, express cytotoxic mediators, and mediate killing of target cells. We also demonstrate that these clonally expanded GZMB+CD8+ cells are present in RA synovium. These findings suggest that cytotoxic CD8+ T cells targeting citrullinated antigens contribute to synovitis and joint tissue destruction in ACPA+ RA.
View details for DOI 10.1038/s41467-022-35264-8
View details for PubMedID 36658110
View details for PubMedCentralID PMC9852471
Intranasal administration of nucleus-deliverable GATA3-TMD alleviates the symptoms of allergic asthma
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
2023; 640: 32-39
Although the T helper 2 (Th2) subset is a critical player in the humoral immune response to extracellular parasites and suppression of Th1-mediated inflammation, Th2 cells have been implicated in allergic inflammatory diseases such as asthma, allergic rhinitis, and atopic dermatitis. GATA binding protein 3 (GATA3) is a primary transcription factor that mediates Th2 differentiation and secretion of Th2 cytokines, including IL-4, IL-5, and IL-13. Here, a nucleus-deliverable form of GATA3-transcription modulation domain (TMD) (ndG3-TMD) was generated using Hph-1 human protein transduction domain (PTD) to modulate the transcriptional function of endogenous GATA3 without genetic manipulation. ndG3-TMD was shown to be efficiently delivered into the cell nucleus quickly without affecting cell viability or intracellular signaling events for T cell activation. ndG3-TMD exhibited a specific inhibitory function for the endogenous GATA3-mediated transcription, such as Th2 cell differentiation and Th2-type cytokine production. Intranasal administration of ndG3-TMD significantly alleviated airway hyperresponsiveness, infiltration of immune cells, and serum IgE level in an OVA-induced mouse model of asthma. Also, Th2 cytokine secretion by the splenocytes isolated from the ndG3-TMD-treated mice substantially decreased. Our results suggest that ndG3-TMD can be a new therapeutic reagent to suppress Th2-mediated allergic diseases through intranasal delivery.
View details for DOI 10.1016/j.bbrc.2022.11.095
View details for Web of Science ID 000927575800005
View details for PubMedID 36502629
Rheumatoid Arthritis Patient-derived Anti-citrullinated Protein Antibodies (ACPAs) Ameliorate Joint Inflammation in Early Collagen-antibody Induced Arthritis (CAIA)
WILEY. 2022: 69-70
View details for Web of Science ID 000877386500045
Clonally Expanded B Cells in Multiple Sclerosis Bind EBV EBNA1 and GlialCAM.
Multiple sclerosis (MS) is a heterogenous autoimmune disease in which autoreactive lymphocytes attack the myelin sheath of the central nervous system (CNS). B lymphocytes in the cerebrospinal fluid (CSF) of MS patients contribute to inflammation and secrete oligoclonal immunoglobulins1,2. Epstein-Barr virus (EBV) infection has been linked to MS epidemiologically, but its pathological role remains unclear3. Here we demonstrate high-affinity molecular mimicry between the EBV transcription factor EBNA1 and the CNS protein GlialCAM, and provide structural and in-vivo functional evidence for its relevance. A cross-reactive CSF-derived antibody was initially identified by single-cell sequencing of the paired-chain B cell repertoire of MS blood and CSF, followed by protein microarray-based testing of recombinantly expressed CSF-derived antibodies against MS-associated viruses. Sequence analysis, affinity measurements, and the crystal structure of the EBNA1-peptide epitope in complex with the autoreactive Fab fragment allowed for tracking the development of the naïve EBNA1-restricted antibody to a mature EBNA1/GlialCAM cross-reactive antibody. Molecular mimicry is facilitated by a post-translational modification of GlialCAM. EBNA1 immunization exacerbates the mouse model of MS and anti-EBNA1/GlialCAM antibodies are prevalent in MS patients. Our results provide a mechanistic link for the association between MS and EBV, and could guide the development of novel MS therapies.
View details for DOI 10.1038/s41586-022-04432-7
View details for PubMedID 35073561