T Lymphocytes in Patients With Nijmegen Breakage Syndrome Demonstrate Features of Exhaustion and Senescence in Flow Cytometric Evaluation of Maturation Pathway

Abstract

Patients with Nijmegen Breakage Syndrome (NBS) suffer from recurrent infections due to humoral and cellular immune deficiency. Despite low number of T lymphocytes and their maturation defect, the clinical manifestations of cell-mediated deficiency are not as severe as in case of patients with other types of combined immune deficiencies and similar T cell lymphopenia. In this study, multicolor flow cytometry was used for evaluation of peripheral T lymphocyte maturation according to the currently known differentiation pathway, in 46 patients with genetically confirmed NBS and 46 sex and age-matched controls. Evaluation of differential expression of CD27, CD31, CD45RA, CD95, and CD197 revealed existence of cell subsets so far not described in NBS patients. Although recent thymic emigrants and naïve T lymphocyte cell populations were significantly lower, the generation of antigen-primed T cells was similar or even greater in NBS patients than in healthy controls. Moreover, the senescent and exhausted T cell populations defined by expression of CD57, KLRG1, and PD1 were more numerous than in healthy people. Although this hypothesis needs further investigations, such properties might be related to an increased susceptibility to malignancy and milder clinical course than expected in view of T cell lymphopenia in patients with NBS.

Lower Humoral and Cellular Immunity following Asymptomatic SARS-CoV-2 Infection in Education (The ACE Cohort)

“…Thus, an increased population in symptomatic adults indicates a higher potential to generate CD4 + memory cells, and subsequently a longer-lasting immune memory. Furthermore, research suggests this population may in fact be revertants; CD4 + memory T cells reverting back to a 'naïve' phenotype upon activation (42)(43)(44), as unlike conventional naïve T cells, this CD4 + subset are activated and producing IL-2.…”

Genetic Disorders with Predisposition to Paediatric Haematopoietic Malignancies—A Review

“…A profound immunodeficiency of both cellular and humoral responses is observed in most patients. In addition to mutations in the NBN gene, an increased susceptibility to lymphoid malignancies can be explained by affected T-cell development with the presence of senescence signs in circulating T-lymphocytes expressing CD57, KLRG1, and PD1 [ 26 ]. Moreover, impaired telomeric repair with telomere attrition and a statistically lower total antioxidant status influences the carcinogenesis [ 27 ].…”

Diagnostic and therapeutic approach to children with Nijmegen breakage syndrome in relation to development of lymphoid malignancies

“…Although recent thymic emigrants and naïve T lymphocyte cell populations are significantly lower, the generation of antigen-primed (effector) T-cells is similar or even greater in NBS patients than in healthy control. There is high frequency of the more differentiated T cells expressing the senescent cell marker CD57, KLRG1, PD1 and do not express co-stimulatory molecule CD28 [5,6]. Such properties might be related to increased susceptibility to lymphoid malignancies.…”

“…The NBN gene codes for nibrin which is involved in DNA double-strand break repair [4]. Due to mutation, V(D)J rearrangement of T cells is affected and circulating T cells have signs of senescence in the young patients with NBS [5,6].…”