Anti-CD4 treatment inhibits autoimmunity in scurfy mice through the attenuation of co-stimulatory signals.
A major concept in autoimmunity is that disruption of Foxp3(+) regulatory T cells (Tregs) predisposes to breach of tolerance. This is exemplified by the Foxp3-linked disorder termed IPEX (immunodysregulation, polyendocrinopathy, enteropathy, X-linked) which affects newborn children. There has been considerable clinical interest in the role of non-depleting anti-CD4 antibodies as a means of upregulating the function of Foxp3(+) Tregs in order to control detrimental inflammatory responses such as transplant rejection. However, according to the paradigm of a Treg-dependent mechanism of action, the effectiveness of anti-CD4 antibodies as a therapy for human autoimmune diseases is unclear considering that Treg function might be intrinsically impaired. Specifically, anti-CD4 therapy is expected to fail in patients suffering from the IPEX syndrome due to the lack of functional Foxp3(+) Tregs. Taking advantage of natural Foxp3 mutant scurfy (sf) mice closely resembling the IPEX syndrome, and genetically engineered mice depleted of Foxp3(+) Tregs, we report here that anti-CD4 treatment induces tolerance independent of Foxp3(+) Tregs. This so far undefined mechanism is dependent on the recessive non-infectious tolerization of autoreactive T cells. Treg-independent tolerance alone is powerful enough to suppress both the onset and severity of autoimmunity and reduces clinically relevant autoantibody levels and liver fibrosis. Mechanistically, tolerance induction requires the concomitant activation of autoreactive T cells and is associated with the down-regulation of the co-stimulatory TNF-receptor superfamily members OX40 and CD30 sustaining CD4(+) T cell survival. In the light of ongoing clinical trials, our results highlight an unexpected potency of anti-CD4 antibodies for the treatment of autoimmune diseases. Particularly, CD4 blockade might represent a novel therapeutic option for the human IPEX syndrome.
Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, Feodor-Lynen-Str. 7, 30625 Hannover, Germany(1).
C T
CT
Mayer
Autoimmune Genetics Laboratory, VIB, Campus Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium; Department of Immunology and Microbiology, University of Leuven, Leuven, Belgium.
L
L
Tian
Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, Feodor-Lynen-Str. 7, 30625 Hannover, Germany(1).
C
C
Hesse
Department of Gastroenterology, Infectiology and Rheumatology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, D-12200 Berlin, Germany.
A A
AA
Kühl
Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, Feodor-Lynen-Str. 7, 30625 Hannover, Germany(1).
M
M
Swallow
Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, Feodor-Lynen-Str. 7, 30625 Hannover, Germany(1).
F
F
Kruse
Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, Feodor-Lynen-Str. 7, 30625 Hannover, Germany(1).
M
M
Thiele
Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, 451 Health Sciences Drive, Suite 6510, Davis, CA 95616, USA.
M E
ME
Gershwin
Autoimmune Genetics Laboratory, VIB, Campus Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium; Department of Immunology and Microbiology, University of Leuven, Leuven, Belgium.
A
A
Liston
Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, Feodor-Lynen-Str. 7, 30625 Hannover, Germany(1). Electronic address: tim.sparwasser@twincore.de.
T
T
Sparwasser
D000818:Animals; D000961:Antilymphocyte Serum / Q000494:pharmacology*; D015551:Autoimmunity / Q000187:drug effects*; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology*; D002470:Cell Survival; D003922:Diabetes Mellitus, Type 1 / Q000151:congenital; D003967:Diarrhea; D004195:Disease Models, Animal; D005260:Female; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D040181:Genetic Diseases, X-Linked / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000473:pathology; D006801:Humans; D007154:Immune System Diseases / Q000151:congenital; D007108:Immune Tolerance / Q000187:drug effects; D017730:Ki-1 Antigen / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D053262:Receptors, OX40 / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology
D000961:Antilymphocyte Serum; D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D017730:Ki-1 Antigen; D053262:Receptors, OX40; C505717:Tnfrsf4 protein, mouse
Anti-CD4; Autoimmunity; Foxp3; IPEX; Scurfy; YTS177.9