Overexpression of CD45RA isoforms in carriers of the C77G mutation leads to hyporeactivity of CD4+CD25highFoxp3+ regulatory T cells.
Disorders in regulatory T-cell (T(reg)) function can result in the breakdown of immunological self-tolerance. Thus, the identification of mechanisms controlling the activity of T(reg) is of great relevance. We used T(reg) from individuals carrying the C77G polymorphism as models to study the role of CD45 molecules in humans. C77G prevents splicing of CD45 exon A thereby leading to an aberrant expression pattern of CD45 isoforms in affected individuals. Resting and in vitro expanded/activated CD4(+)CD25(high)Foxp3(+) T(reg) from carriers of C77G strongly expressed CD45RA isoforms whereas these isoforms were almost absent in cells from individuals with wild-type CD45. C77G T(reg) showed diminished upregulation of activation markers, lower phosphorylation of p56(lck)(Y505) and a reduced proliferative potential when stimulated with anti-TcR or anti-TcR plus CD28 mAb suggesting decreased responsiveness to activating stimuli. In addition, the capacity to suppress proliferation of conventional CD4(+) T cells was impaired in C77G T(reg). Furthermore, microarray studies revealed distinct gene expression patterns in T(reg) from C77G carriers. These data suggest that the changes in CD45 isoform combination resulting from the C77G mutation alter the responsiveness of T(reg) to TcR-mediated signaling. Targeting CD45 isoform expression might be a useful approach to modulate T(reg) function.
Transplant Laboratory, Department of General, Visceral, and Transplantation Surgery, Hannover Medical School, Hannover, Germany.
C
C
Pokoyski
Transplant Laboratory, Department of General, Visceral, and Transplantation Surgery, Hannover Medical School, Hannover, Germany.
T
T
Lienen
Transplant Laboratory, Department of General, Visceral, and Transplantation Surgery, Hannover Medical School, Hannover, Germany.
S
S
Rother
Transplant Laboratory, Department of General, Visceral, and Transplantation Surgery, Hannover Medical School, Hannover, Germany.
E
E
Schock
Transplant Laboratory, Department of General, Visceral, and Transplantation Surgery, Hannover Medical School, Hannover, Germany.
A
A
Plege-Fleck
Research Group Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany.
R
R
Geffers
Transplant Laboratory, Department of General, Visceral, and Transplantation Surgery, Hannover Medical School, Hannover, Germany.
R
R
Schwinzer
D018106:CD28 Antigens / Q000378:metabolism; D049109:Cell Proliferation; D006801:Humans; D007108:Immune Tolerance; D017493:Leukocyte Common Antigens / Q000235:genetics* / Q000276:immunology*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D009154:Mutation; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*
D018106:CD28 Antigens; D020033:Protein Isoforms; D011948:Receptors, Antigen, T-Cell; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D017493:Leukocyte Common Antigens