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Defects of T-Cell Receptor Signaling

المؤلف:  Hoffman, R., Benz, E. J., Silberstein, L. E., Heslop, H., Weitz, J., & Salama, M. E.

المصدر:  Hematology : Basic Principles and Practice

الجزء والصفحة:  8th E , P740

2026-07-29

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 Several forms of combined immune deficiency are caused by genetic defects that affect the following molecules involved in TCR signaling. In particular, the T lymphocyte-specific protein tyro sine kinase (Lck) associates with CD4 and CD8 molecules and mediates phosphorylation of CD3 chains upon TCR engagement. The Zeta-associated protein of 70 kDa (ZAP-70) tyrosine kinase phosphorylates the CD3 chains, thus promoting downstream TCR signaling. RHOH is an atypical Rho GTPase that participates in receptor-induced signaling in hematopoietic cells. The IL-2-inducible tyrosine kinase (ITK) is a member of the family of nonreceptor tyro sine kinases, and modulates the strength of the TCR-induced signal. The serine-threonine protein kinase 4 (STK4) protein induces the transcriptional coactivation of target genes involved in cell proliferation and survival and is involved in the control of cell death.

At variance with typical forms of SCID, genetic defects of TCR signaling are characterized by residual numbers and/or function of T cells, consistent with partially preserved thymic architecture and function. Since the thymus of these patients is not empty, the use of chemotherapy is required to facilitate engraftment and T-cell differentiation with donor-derived cells. The immunological phenotype of ZAP-70 deficiency in humans is characterized by a virtual lack of CD8+ lymphocytes; the number of CD4+ cells is preserved, but they are unable to proliferate in response to mitogens and anti gens. In contrast, both CD4+ and CD8+ lymphocytes are absent in Zap70–/– mice.

Both Ras homolog family member H (RHOH) and STK4 deficiencies are characterized by a reduced number of naïve T cells, an increased proportion of effector memory T-cells (including CD8+ cells with an “exhausted” CD45RA+CCR7– phenotype), and defective lymphocyte proliferation. CD4 lymphopenia and low levels of CD4 and CD8 surface expression have been reported in LCK deficiency. Progressive CD4 lymphopenia is also commonly seen in patients with ITK deficiency.

Each of these forms of impaired TCR signaling are inherited as autosomal recessive traits. Clinically, patients with impaired T-cell signaling present with recurrent, often severe, infections. Cutaneous viral infections are especially common in patients with RHOH and STK4 deficiency. The clinical phenotype of ZAP-70 deficiency is often undistinguishable from SCID; in a few cases, hypomorphic ZAP70 mutations have been associated with Omenn syndrome. Severe lung disease and a high risk of EBV-driven lymphoproliferation are a hallmark of ITK deficiency. Autoimmune manifestations have been observed in several patients with these disorders. Prevention of infections is based on antimicrobial prophylaxis and use of intravenous immunoglobulins; however, ultimate treatment requires SCT.

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