RESUMEN

The CTLA-4 checkpoint regulates the activation of T cells. Individuals with heterozygous mutations in CTLA-4 have a complex phenotype typically characterized by antibody deficiency alongside variable autoimmunity. Despite severe disease in some individuals, others remain largely unaffected with reasons for this variation unknown. We studied a large family carrying a single point mutation in CTLA-4 leading to an amino acid change R75W and compared both unaffected with affected individuals. We measured a variety of features pertaining to T cell and CTLA-4 biology and observed that at the cellular level there was complete penetrance of CTLA-4 mutations. Accordingly, unaffected individuals were indistinguishable from those with disease in terms of level of CTLA-4 expression, percentage of Treg, upregulation of CTLA-4 upon stimulation and proliferation of CD4 T cells. We conclude that the wide variation in disease phenotype is influenced by immune variation outside of CTLA-4 biology.

Asunto(s)

Antígenos CD28/inmunología , Antígeno CTLA-4/inmunología , Activación de Linfocitos/inmunología , Linfocitos T/inmunología , Antígenos CD28/metabolismo , Antígeno CTLA-4/deficiencia , Antígeno CTLA-4/genética , Diarrea/genética , Diarrea/inmunología , Diarrea/metabolismo , Salud de la Familia , Femenino , Humanos , Enfermedades Intestinales/genética , Enfermedades Intestinales/inmunología , Enfermedades Intestinales/metabolismo , Activación de Linfocitos/genética , Masculino , Mutación Missense , Linaje , Índice de Severidad de la Enfermedad , Transducción de Señal/inmunología , Linfocitos T/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo