Strong adaptive immunity in humans with inherited CD4 deficiency

Abstract

Abstract Since the early 1970s when the T cell receptor was first characterized, the role of human CD4 in adaptative immunity has been extensively studied, especially in the context of HIV infection and inborn error of immunity (e.g. HLA class II deficiency). Nonetheless, it was only recently (2019, 2021) that patients with inactivating germline mutations in CD4has been described. Herein, we present five novel patients from three unrelated kindred with bi-allelic rare variants in CD4. Consistent with previous studies, patients showed a broad spectrum of clinical infectious susceptibility which was rather mild given their lack of detectable CD4 +T cells in peripheral blood mononuclear cells (PBMCs). Despite an almost unremarkable immunophenotype, patient’s PBMCs were characterized by the expansion of an enigmatic CD4 −CD8 −(DN) TCRαβ +T cells population which retained some functional characteristic of typical CD4 +T cells. We observed that the patient’s DN cells transcriptionally (Sc-RNAseq) and functionally (cytokine production/secretion) were comparable to that of healthy donor CD8 −T cells. Interestingly, using cutting-edge long-read sc-RNAseq technology we revealed that patient’s DN cells expressed normal TCR repertoires, and paired TCRαβ sequences comparable to healthy donor CD4 +T cells. Furthermore, via biochemical studies we identified a CD4alternative transcript expressed in patient’s PBMCs (also detected in healthy donor cells) leading to the surface expression of an unreported CD4 shorter isoform which is not detectable with conventional CD4 antibodies. To conclude, our study not only characterizes novel CD4-deficient patients, but also reveals alternative CD4 isoform expression and its compensatory role in immunity. AAI Careers in Immunology Fellowship 2022 (RG222573)