A Novel Thymoma-Associated Immunodeficiency with Increased Naive T Cells and Reduced CD247 Expression

Abstract

The mechanisms underlying thymoma-associated immunodeficiency are largely unknown, and the significance of increased blood γδ Τ cells often remains elusive. In this study we address these questions based on an index patient with thymoma, chronic visceral leishmaniasis, myasthenia gravis, and a marked increase of rare γδ T cell subsets in the peripheral blood. This patient showed cutaneous anergy, even though he had normal numbers of peripheral blood total lymphocytes as well as CD4+ and CD8+ T cells. Despite his chronic infection, analyses of immunophenotypes and spectratyping of his lymphocytes revealed an unusual accumulation of naive γδ and αβ T cells, suggesting a generalized T cell activation defect. Functional studies in vitro demonstrated substantially diminished IL-2 and IFN-γ production following TCR stimulation of his “untouched” naive CD4+ T cells. Biochemical analysis revealed that his γδ and αβ T cells carried an altered TCR complex with reduced amounts of the ζ-chain (CD247). No mutations were found in the CD247 gene that encodes the homodimeric ζ protein. The diminished presence of CD247 and increased numbers of γδ T cells were also observed in thymocyte populations obtained from three other thymoma patients. Thus, our findings describe a novel type of a clinically relevant acquired T cell immunodeficiency in thymoma patients that is distinct from Good’s syndrome. Its characteristics are an accumulation of CD247-deficient, hyporresponsive naive γδ and αβ T cells and an increased susceptibility to infections.

Comment on “A Novel Thymoma-Associated Immunodeficiency with Increased Naive T Cells and Reduced CD247 Expression”

“…Comment on "A Novel ThymomaAssociated Immunodeficiency with Increased Naive T Cells and Reduced CD247 Expression" W e read with great interest the paper by Christopoulos et al (1). We suspect that the significance of their discovery could reach far beyond what the authors proposed in their seminal paper.…”

“…W e thank Dr. Welch and Dr. Howard for their comments on our recent study (1). CD247, a subunit of the TCRab and TCRgd, is often downmodulated in effector and memory T cells in animals and patients with chronic inflammatory conditions such as autoimmune and infectious diseases, as well as cancer (2).…”

Deficient CD247 expression is a typical histopathological characteristic of thymomas with cortical features

“…Theoretically, this might result in a greater impairment of immune function, because naive T cells are less efficient in the acquisition of effector capabilities after TCR stimulation than memory cells. Indeed, we have demonstrated TCR hyporesponsiveness of CD247‐deficient naive T cells in a thymoma patient with chronic infection and myasthenia gravis, while other investigators have observed impaired T cell mitogen responses and cutaneous anergy in thymoma patients with myasthenia gravis and/or increased infections . Furthermore, a potential role of acquired CD247 deficiency in the pathogenesis of thymoma‐related autoimmunity is suggested by the observation that genetic variations and polymorphisms of the CD247 gene resulting in reduced CD247 function cause autoimmune disorders in humans and mice, such as type I diabetes, systemic lupus erythematosus and rheumatoid arthritis .…”

“…Sir : Autoimmune disorders and infections are frequent complications of thymomas, but their pathogenesis remains poorly understood. Prompted by the observation of expanded naive hyporesponsive T cells in the blood of a thymoma patient with chronic visceral leishmaniasis and myasthenia gravis, we recently described an acquired CD247 deficiency in isolated thymocytes of a few index thymoma patients with autoimmunity and/or chronic infection . CD247 is an invariant chain of the T cell receptor (TCR) complex with a critical role in intracellular signal transduction, and its down‐regulation impairs antigen‐dependent T cell activation .…”

Response to Comment on “A Novel Thymoma-Associated Immunodeficiency with Increased Naive T Cells and Reduced CD247 Expression”

“…Response to Comment on "A Novel Thymoma-Associated Immunodeficiency with Increased Naive T Cells and Reduced CD247 Expression" W e thank Dr. Welch and Dr. Howard for their comments on our recent study (1). CD247, a subunit of the TCRab and TCRgd, is often downmodulated in effector and memory T cells in animals and patients with chronic inflammatory conditions such as autoimmune and infectious diseases, as well as cancer (2).…”