The 77C→G Mutation in the Human CD45 (PTPRC) Gene Leads to Increased Intensity of TCR Signaling in T Cell Lines from Healthy Individuals and Patients with Multiple Sclerosis

Abstract

The 77C→G mutation in exon A of the human CD45 gene occurs with low frequency in healthy individuals. An enhanced frequency of 77C→G individuals has been reported in cohorts of patients suffering from multiple sclerosis, systemic sclerosis, autoimmune hepatitis, and HIV-1. To investigate the mechanisms by which the variant allele may contribute to disease susceptibility, we compared T cell reactivity in heterozygous carriers of the mutation (healthy individuals and multiple sclerosis patients) and wild-type controls. In vitro-generated T cell lines and freshly isolated CD4+CD45R0+ primed/memory T cells from 77C→G individuals aberrantly expressed CD45RA isoforms and showed enhanced proliferation and IL-2 production when stimulated with anti-TCR/CD3 mAb or Ag. Mutant T cell lines contained a more active pool of p56lck tyrosine kinase and responded with increased phosphorylation of Zap70 and TCR-ζ and an enhanced Ca2+ flux to TCR/CD3 stimulation. These data suggest that 77C→G may act as a risk factor for certain diseases by increasing the intensity of TCR signaling.

HIV–TB coinfection impairs CD8+ T‐cell differentiation and function while dehydroepiandrosterone improves cytotoxic antitubercular immune responses

“…1C), which could contribute to the increased T TE proportions observed in these patients. However, we observed lower levels of CD45RA on CD8 + T cells in HIV-TB patients, compared to HD, that may reflect a lower cell responsiveness, since an enhancing role for CD45RA in TCR signaling in multiple sclerosis and in the human cell line Jurkat has been described [27][28][29]. Similarly, HIV infection induces a maturation defect on HIV-specific T TE cells, which may represent an HIV-induced evasion mechanism [34].…”

“…2B and C). This lower expression of CD45RA in bulk CD8 + T TE cells from HIV-Mtb coinfected patients may reduce responsiveness in these cells since CD45RA enhances TCR signaling [28,29].During HIV infection, PD-1 expression is a marker for abnormal naïve/memory distribution in T cells [30]. We observed an increment in PD1 expression on bulk CD8 + T cells among HIV-TB and HIV + patients compared to HD (Fig.…”

“…2B and C). This lower expression of CD45RA in bulk CD8 + T TE cells from HIV-Mtb coinfected patients may reduce responsiveness in these cells since CD45RA enhances TCR signaling [28,29].…”

Unusual case presentations associated with the CD45 C77G polymorphism

“…Nor, although there are several syndromes associating cardiac and immunological abnormalities [35,36], do we have any information on the clinical status of the patient, as we could not obtain this for ethical reasons. Discovery of C77G in all these patients may be an incidental finding but the evidence that immune function is abnormal in humans and experimental animals with altered CD45 expression suggests that these polymorphisms may contribute to disease pathogenesis [21][22][23]28,37,38].…”

“…An increased frequency of C77G has been found in HIV [14], Langerhans cell histiocytosis [15], systemic sclerosis [16], hepatitis C [17] and autoimmune hepatitis [18], but no association with common variable immunodeficiency (CVID), Graves' disease or diabetes [10,19,20]. Furthermore, C77G individuals show lymphocyte functional abnormalities, including increased IL-2 production by memory CD4 T cells and an altered threshold for signalling through the T-cell receptor [21,22]. Another polymorphism of CD45, A138G in exon 6, is also associated with altered disease susceptibility and immune function [23,24], and absence of CD45 is also a cause of severe combined immunodeficiency [25][26][27] There is therefore abundant evidence that altered CD45 expression affects the immune function in man, as in experimental animals [28].…”