Molecular Classification of Primary Immunodeficiencies of T Lymphocytes

Abstract

Proper regulation of the immune system is required for protection against pathogens and preventing autoimmune disorders. Inborn errors of the immune system due to inherited or de novo germline mutations can lead to the loss of protective immunity, aberrant immune homeostasis, and the development of autoimmune disease, or combinations of these. Forward genetic screens involving clinical material from patients with primary immunodeficiencies (PIDs) can vary in severity from life-threatening disease affecting multiple cell types and organs to relatively mild disease with susceptibility to a limited range of pathogens or mild autoimmune conditions. As central mediators of innate and adaptive immune responses, T cells are critical orchestrators and effectors of the immune response. As such, several PIDs result from loss of or altered T cell function. PID-associated functional defects range from complete absence of T cell development to uncontrolled effector cell activation. Furthermore, the gene products of known PID causal genes are involved in diverse molecular pathways ranging from T cell receptor signaling to regulators of protein glycosylation. Identification of the molecular and biochemical cause of PIDs can not only guide the course of treatment for patients, but also inform our understanding of the basic biology behind T cell function. In this chapter, we review PIDs with known genetic causes that intrinsically affect T cell function with particular focus on perturbations of biochemical pathways.

Introduction

This theme has been at the centre of all my research…, both because of its intrinsic fascination and my conviction that a knowledge of sequences could contribute much to our understanding of living matter.

Frederick Sanger

T lymphocyte cells (T cells) play a central role in the adaptive immune response, coordinating immune functions comprising both humoral and cell-mediated responses to a myriad of immunogenic challenges including infection and cancer. Therefore, understanding how these cells work in humans requires a detailed molecular approach combining cellular immunology, clinical investigation, and human genetics. Normally, mechanisms of central and peripheral tolerance limit the response to self, thus preventing autoimmune disease. These varied and at times conflicting roles require many levels of control to appropriately modulate T cell-mediated immune responses. These include regulation of T cell development, maintenance of quiescence and self-tolerance, initiation and maintenance of T cell activation in response to cognate antigen, migration to effector sites, effector function, differentiation, and maintenance of a memory population. Multiple genes regulate these steps in ways critical to proper immune responses. One method of identifying important regulators of T cell function is a genetic approach involving the investigation of individuals with inborn errors of immunity. These primary immunodeficiencies (PIDs) result in diverse and overlapping clinical phenotypes including immunodeficiency (susceptibility to malignancy or infection), abnormal cellular homeostasis, autoimmunity, autoinflammation, and allergy. PIDs represent a forward genetic screen of nature, meaning that a phenotype is first identified—often provoked by infectious and noninfectious immunological challenges that the patients encounter—and then the pathophysiological attributes in immunity and ultimately gene variants that correlate with disease are interrogated. Within the last decade, the development of inexpensive technologies for sequencing the DNA of the human genome or exome (the coding portion of the genome) have allowed for the rapid identification of the genetic variants underlying various PIDs. This coupled with the vast reach of clinical medicine to identify, characterize, and follow longitudinally patient phenotypes has facilitated a powerful new approach to understand the effect of genotype variation on human immune function. In this chapter, we will discuss the biochemical and molecular basis of disease in PIDs caused in whole or in part by defects in T cell function.