Dyskeratosis congenita (DC) is an inherited bone marrow failure disorder characterized by abnormal skin pigmentation and nail dystrophy. We have recently described, in 10 members of a large 3-generation family, an autosomal-dominant form of DC (AD DC) that is due to a mutation in the gene-encoding human telomerase RNA (TERC), resulting in telomere shortening. In studying the immunologic consequences of TERC mutations, severe B lymphopenia and decreased immunoglobulin M (IgM) levels were noted. T cells were found to overexpress senescent markers, including CD57 and Fas receptor, and were moderately reduced in cell number. To determine whether these in vivo findings were related to cellular replicative defects, short-term cultures of AD DC lymphocytes were established to measure proliferation, mitoses, and apoptosis. AD DC lymphocytes displayed a markedly reduced proliferative capacity and increased basal apoptotic rate. Finally, telomere shortening was most prominent in third-generation subjects, and there appeared to be a correlation between telomere length and in vivo and in vitro immune findings. In summary, the observed lymphopenia and hypogammaglobulinemia in AD DC is likely a consequence of replicative failure and premature senescence of lymphocytes, supporting a role of telomerase activity in immune homeostasis. © 2005 by The American Society of Hematology.