RLTPR deficiency : a new genetic etiology of combined immunodeficiency

Abstract : Combined immunodeficiency (CID) refers to inborn errors of human T cells that also affect B cells, due to the T cell deficit or an additional B cell-intrinsic deficit. The identification of new genetic etiologies of CID is important to better understand the immune responses to infectious agents in humans, and to better manage patients with infectious diseases. We herein report 6 patients from 3 unrelated families (Moroccan, Tunisian and Turkish) with bi-allelic mutations in RLTPR, the mouse orthologue of which is essential for CD28 signaling. The patients developed a variety of infections, including invasive tuberculosis and mucocutaneous candidiasis but also presented cutaneous and pulmonary allergic manifestations. The identification of autosomal recessive RLTPR deficiency elucidates a new genetic etiology for CID patients. This work focused on the role of human RLTPR in T cell and B cell immunity. In RLTPR-deficient patients, proportions of circulating regulatory T cells, memory CD4+ T cells and central memory CD8+ T cells are reduced. In vitro, proliferation of patients’ T cells is diminished in response to various stimuli, including mitogens and antigens. The RLTPR-deficient CD4+ T cells did not respond to CD28 stimulation in terms of the production of IFN-γ, TNF and IL-2, as well as the phosphorylation of P65. The CD4+ T cells exhibit a Th2 bias ex vivo and when cultured in vitro, contrasting with the paucity of Th1, Th17, and Tfh cells. The patients also displayed a deficiency of memory B cells and poor Ab responses. This B cell phenotype does not result solely from the T cell deficiency, as the patients’ B cells fail to activate NF-κB upon BCR stimulation. Our study strongly suggests that human RLTPR deficiency is a CID affecting at least the CD28 responsive pathway in T cells and the BCR responsive pathway in B cells.
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Yi Wang. RLTPR deficiency : a new genetic etiology of combined immunodeficiency. Immunology. Université Sorbonne Paris Cité, 2016. English. ⟨NNT : 2016USPCB111⟩. ⟨tel-02145632⟩

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