The Role of Follicular Helper T Cell Molecules and Environmental Influences in Autoantibody Production and Progression to Inflammatory Arthritis in Mice.
OBJECTIVE
Antibody-mediated autoimmunity involves cognate interactions between self-reactive T cells and B cells during germinal center (GC) reactions. The aim of this study was to determine the role of essential follicular helper T (Tfh) cell molecules (CXCR5, signaling lymphocytic activation molecule-associated protein) on autoreactive CD4+ cells and the role of certain environmental influences that may determine GC-driven autoantibody production and arthritis development.


METHODS
We transferred self-reactive CD4+ cells from KRN-Tg mice into recipient mice, which induced autoantibodies and autoinflammatory arthritis. This model allowed manipulation of environmental effects, such as inflammation, and use of transferred cells that were genetically deficient in important Tfh cell-associated molecules.


RESULTS
A deficiency of signaling lymphocytic activation molecule-associated protein (SAP) in CD4+ cells from KRN-Tg mice completely protected against arthritis, indicating that stable T cell-B cell interactions are required for GC formation, autoantibody production, and arthritis induction. In contrast, a CXCR5 deficiency in CD4+ cells from KRN-Tg mice still induced disease when these cells were transferred into wild-type mice, suggesting that T cell help for B cells could rely on other migration mechanisms. However, various manipulations influenced this system, including elimination of bystander effects through use of CD28(-/-) recipient mice (reduced disease) or use of inflammation-inducing Freund's complete adjuvant (progression to arthritis). We also examined the capacity of preexisting GCs with a nonautoimmune specificity to co-opt autoimmune T cells and observed no evidence for any influence.


CONCLUSIONS
In addition to the quality and quantity of cognate CD4+ cell help, external factors such as inflammation and noncognate CD4+ cell bystander activation trigger autoimmunity by shaping events within autoimmune GC responses. SAP is an essential molecule for autoimmune antibody production, whereas the importance of CXCR5 varies depending on the circumstances.
University Medical Centre Freiburg, Freiburg, Germany, Monash University, Clayton Campus, Melbourne, Victoria, Australia, and Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
Nina
N
Chevalier
Monash University, Clayton Campus, Melbourne, Victoria, Australia, and Charles Perkins Centre, University of Sydney, Camperdown, New South Wales, Australia.
Laurence
L
Macia
Monash University, Clayton Campus, Melbourne, Victoria, Australia.
Jian K
JK
Tan
Monash University, Clayton Campus, Melbourne, Victoria, Australia.
Linda J
LJ
Mason
Monash University, Clayton Campus, Melbourne, Victoria, Australia.
Remy
R
Robert
Monash University, Clayton Campus, Melbourne, Victoria, Australia.
Alison N
AN
Thorburn
Monash University, Clayton Campus, Melbourne, Victoria, Australia.
Connie H Y
CH
Wong
Monash University, Clayton Campus, Melbourne, Victoria, Australia.
Louis M
LM
Tsai
Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
Katherine
K
Bourne
Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
Robert
R
Brink
Monash University, Clayton Campus, Melbourne, Victoria, Australia.
Di
D
Yu
Monash University, Clayton Campus, Melbourne, Victoria, Australia.
Charles R
CR
Mackay
D000818:Animals; D015535:Arthritis, Psoriatic / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology*; D001323:Autoantibodies / Q000096:biosynthesis* / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology; D004195:Disease Models, Animal; D018450:Disease Progression; D004777:Environment; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D018858:Germinal Center / Q000166:cytology; D005956:Glucose-6-Phosphate Isomerase / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D060888:Real-Time Polymerase Chain Reaction; D054380:Receptors, CXCR5 / Q000235:genetics / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D001323:Autoantibodies; C513179:CXCR5 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D054380:Receptors, CXCR5; C499569:Sh2d1a protein, mouse; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D005956:Glucose-6-Phosphate Isomerase