Overexpression of CD45RA isoforms in carriers of the C77G mutation leads to hyporeactivity of CD4+CD25highFoxp3+ regulatory T cells

Abstract

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.

Tetraspanin CD53 controls T cell immunity through regulation of CD45RO stability, mobility, and function

“…*p < 0.05, **p < 0.01. early TCR signaling. In line with this, a known patient mutation of CD45 leading to altered isoform expression (similar to our CD53 À/À phenotype) resulted in only a marginal difference in Y505 phosphorylation (<20%), despite producing a distinct phenotype in T cells (Pokoyski et al, 2015). Finally, it is well known that Lck Y505 phosphorylation status is the result of a balance between dephosphorylation by CD45 and phosphorylation by the Csk tyrosine kinase (Palacios and Weiss, 2004;Zikherman et al, 2010).…”

Modulation of TCR Signaling by Tyrosine Phosphatases: From Autoimmunity to Immunotherapy

“…A similarly enhanced proliferation was seen in response to stimulation with IL-2 (Windhagen et al, 2007). In addition, Tregs from C77G carriers showed impaired responsiveness to TCR/CD28 stimulation and reduced ability to suppress conventional CD4 T cells (Pokoyski et al, 2015). However, the association between the C77G SNP and MS has only been corroborated by some subsequent studies (Ballerini et al, 2002) but not others (Barcellos et al, 2001;Gomez-Lira et al, 2003;Nicholas et al, 2003;Cocco et al, 2004;Szvetko et al, 2009), although this disparity may be because of the case-control design of most primary studies and low allelic frequency in most populations (Tchilian and Beverley, 2006).…”

C77G in PTPRC (CD45) is no risk allele for ovarian cancer, but associated with less aggressive disease

“…Therefore it was tempting to hypothesise that C77G could be associated with ovarian cancer risk in general, although the harbouring gene PTPRC is not expressed in tumour cells, but restricted to lymphocytes. However, it has been reported earlier that enforced expression of CD45RA by C77G can change T cell function in various ways [ 9 – 11 ], which might also influence anti-tumour immune responses. Furthermore, this was supported by a recent observation that the newly described SNP (rs869736) in the promoter region of PTPRCAP , encoding CD45 associated protein (CD45-AP), has been linked to diffuse-type gastric cancer [ 35 ].…”

“…Furthermore, C77G cells proliferate more in response to TCR/CD28 (only the memory CD4 + CD45R0 + cells) and IL-2 stimulation [ 9 , 10 ]. However, an opposite, hypo reactive effect of C77G was recently described for regulatory T cells [ 11 ].…”