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T Cell Immunology for the Clinician

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T Cell Immunology for the Clinician ® CONCISE REVIEWS OF PEDIATRIC INFECTIOUS DISEASES CONTENTS T Cell Immunology for the Clinician EDITORIAL BOARD Co-Editors: Margaret C. Fisher, MD, and Gary D. Overturf, MD Editors for this Issue: Geoffrey A. Weinberg, MD Board Members Michael Cappello, MD Charles T. Leach, MD Jeffrey R. Starke, MD Ellen G. Chadwick, MD Kathleen McGann, MD Geoffrey A. Weinberg, MD Janet A. Englund, MD Jennifer Read, MD Leonard Weiner, MD Leonard R. Krilov, MD Charles R. Woods, MD T Cell Immunology for the Clinician Jennifer L. Nayak, MD,* and Andrea J. Sant, PhD† Key Words: T cells, cell-mediated immunity, Artemis genes, among others) mediates scription factor of thymic medullary epithe- immunodeficiency cleavage and repair of DNA near the V, D, lial cells.8,9 (Pediatr Infect Dis J 2011;30: 248–250) and J segments in a series of coordinated steps. If the gene recombination is produc- tive and the RNA message has no abnormal ANTIGEN RECOGNITION BY T he adaptive immune system is character- stop codons present, the subsequently trans- LYMPHOCYTES Tized by its ability to distinguish self from lated protein chains pair to form the TCR, T cells respond to peptide antigens nonself; responds specifically to encounters which is expressed on the cell surface. Sim- bound to MHC molecules; the peptide anti- with foreign antigens (eg, pathogens); and ilar to immunoglobulin gene rearrangement, gens are either produced in or taken up by develops immunologic memory allowing for tremendous TCR-binding site diversity re- the body’s own cells. CD8ϩ T cells are the a more vigorous response to subsequent sults from this process—the large number of cytotoxic T cells of the adaptive immune challenges with the same antigen. T lympho- possible recombinations of V, D, and J seg- system. They respond to peptides that are 8 cytes play several roles in adaptive immunity, ments provide combinatorial diversity, and to 10 amino acids in length bound specifi- autoimmune disease, and allergy; new additional diversity is conferred by impreci- cally to the peptide-binding groove of MHC T-helper cell subsets continue to be described, sion in the DNA-joining reaction.2,3,7 class I molecules. The MHC class I molecule promising to better explain autoimmune and The maturing T cells can be divided 1–6 is expressed on all nucleated cells in the primary immunodeficiency diseases. into 2 groups depending on the cluster of body. In contrast, CD4ϩ T cells respond to differentiation, or CD, surface markers ex- peptides presented by MHC class II mole- T CELL DEVELOPMENT pressed. If an ␣␤ TCR is expressed at the cell cules, which are only expressed on a limited Bone marrow pluripotent hematopoi- surface, the cell first transitions to a “double subset of host cells—the “professional” an- etic stem cells first give rise to multipotent, positive” T cell, expressing both the CD4 tigen-presenting cells (APCs, including B then to common, lymphoid progenitor cells; and CD8 surface markers. The T cell then cells, macrophages, and dendritic cells). some of the latter further traffic to the thy- undergoes the 2 thymic processes of positive CD4ϩ T cells perform many accessory func- mus for T-cell lymphocyte differentiation.1–3 and negative selection (Fig. 1). Positive se- tions within the immune system; hence, they T cells are marked by the presence of the lection occurs when the TCR binds, with low are generally referred to as “helper” T cells.1 surface-expressed heterodimeric T-cell re- avidity, to a major histocompatibility (MHC) MHC molecules exhibit a vast amount ceptor (TCR) that consists of combinations molecule presenting a self-peptide. T cells of polymorphism in their peptide-binding of either the ␣ and ␤,orthe␥ and ␦ chains. that are not able to bind strongly enough to pockets, and in addition, up to 6 unique The germline TCR genes contain multiple these self-peptide-MHC complexes are elim- MHC class I and 12 unique MHC class II variable (V), diversity (D) (in ␤ and ␥ inated by apoptosis (“death by neglect”). molecules are able to be expressed simulta- genes), and joining (J) segments. The V(D)J Cells positively selected by an MHC class I neously. Together with the diversity of recombinase enzyme complex (including en- molecule become CD8 single-positive, while TCRs, this allows for the binding of the zymes encoded by the RAG1, RAG2, and cells selected through MHC class II mole- tremendous array of pathogen and tumor cell cules become CD4 single-positive. Negative epitopes which the immune system may en- 1,2,7 From the Departments of *Pediatrics and †Micro- selection occurs when a TCR binds with too counter. Although peptides presented on biology and Immunology, University of Roch- great avidity to the self-peptide-MHC; these MHC class I molecules typically are derived ester School of Medicine and Dentistry, Roch- cells are eliminated to ensure that potentially from intracellular and nuclear proteins (eg, ester, NY. 2,3 Copyright © 2011 by Lippincott Williams & Wilkins autoreactive T cells do not persist. Nega- from intracellular viral infection), certain ISSN: 0891-3668/11/3003-0248 tive selection is carried out under the control dendritic cells have the ability to “cross- DOI: 10.1097/INF.0b013e3182074658 of the AIRE (autoimmune regulator) tran- present” antigens derived from extracellular The Concise Reviews of Pediatric Infectious Diseases (CRPIDS) topics, authors, and contents are chosen and approved indepen- dently by the Editorial Board of CRPIDS. 248 | www.pidj.com The Pediatric Infectious Disease Journal • Volume 30, Number 3, March 2011 The Pediatric Infectious Disease Journal • Volume 30, Number 3, March 2011 Concise Reviews Th1 cells are important in cell-medi- ated immune responses, and are able to make IFN␥, TNF␣, and IL-2.2,5 Th1 cells activate macrophages, assist in the clearance of intra- cellular pathogens, and mediate delayed-type hypersensitivity responses. Cytokine produc- tion by Th1 cells is also important in B cell class switching to immunoglobulin isotypes that are useful for neutralization of toxins and viruses. Th2 cells play a central role in medi- ating immunity to parasitic infections.17 In- appropriate activation of this CD4ϩ T-cell differentiation pathway has also been strongly implicated in the development of asthma and allergy. Cytokines produced by FIGURE 1. Summary of ␣␤ T-cell receptor (TCR)-expressing T cell development in Th2 cells include IL-4, IL-5, IL-9, and IL-13. the thymus. These cytokines play an important part in the recruitment of eosinophils (IL-5) and mast cells (IL-9). Th2 cells are also able to regu- ϩ ϩ development of long-lived, functional CD8 late B cell class switching to IgE; in turn, IgE sources to CD8 T cells. This allows naive 12,13 ϩ memory T cells. This memory has been immune complexes activate recruited ba- cytotoxic CD8 lymphocytes to be activated broadly divided into central and effector sophils and mast cells, resulting in their de- even when a pathogen does not cause an memory. Central memory cells reside in granulation and the release of cytokines, che- intracellular infection in APCs, or when a lymphoid organs, where they proliferate rap- 10 mokines, histamine, heparin, serotonin, and tumor is not APC-derived. Similarly, al- idly in response to antigen re-exposure, but proteases. though class II MHC molecules are classi- do not have immediate lytic function. Effec- Th17 cells are important in clearance cally described as presenting peptides im- tor memory cells are found in nonlymphoid of extracellular pathogens, including Can- ported from the cell surface (eg, from tissues and are able to express immediate dida albicans and Staphylococcus aureus, extracellular infection), more recent data lytic activity on recall. These cells can be especially from the skin and lungs. However, demonstrate that the process of autophagy rapidly recalled on re-exposure to antigen, Th17 cells have also been implicated in the allows intracellular and nuclear pathogens to 12,13 resulting in rapid pathogen clearance. development of autoimmune diseases, in- also access the endosomal network and be ϩ ϩ Therefore, activation of CD8 cells through cluding inflammatory bowel disease, psoria- presented to CD4 T cells through MHC antigen encounter elicits both robust effec- sis, multiple sclerosis and systemic lupus class II molecules.11 tor function capable of selective pathogen erythematosus, as well as in chronic allergic elimination at the site of infection, and the inflammatory processes such as asthma. T LYMPHOCYTE EFFECTOR development of specific memory cells that Th17 cells are able to produce multiple cy- FUNCTIONS are able to be rapidly mobilized upon fu- tokines, including IL-17 (important in the -؉ ture encounter with the original or a related recruitment of neutrophils) and IL-22 (im CD8 T Cells pathogen. Such immunologic memory During an immune response, naive portant in the production of antimicrobial plays an important role in the immune 5,6,18 cytotoxic CD8ϩ T cells responding to anti- defensins). response to vaccination. Tregs are critical for the maintenance gen undergo rapid clonal expansion within ؉ the draining lymph node, with the resulting CD4 T Cells of self-tolerance and immune homeostasis, generation of a large number of antigen- CD4ϩ T cells provide help to B cells, promoting the contraction of the immune specific T cells. These cells can express che- enabling both class switching and production response after pathogen clearance. They mokine receptors that allow them to travel to of high-affinity antibodies, initiate and main- function not only to prevent autoimmunity, sites of inflammation or infection. There they tain CD8ϩ T-cell responses, regulate macro- immune-mediated damage, and allergy, but bring about pathogen clearance by secreting phage function, and also directly mediate can also suppress antitumor immune re- 15 effector cytokines such as IFN␥ and TNF␣, pathogen clearance.
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