Immune repertoire

Last updated

The immune repertoire encompasses the different sub-types an organism's immune system makes of immunoglobulins or T-cell receptors. These help recognise pathogens in most vertebrates. The sub-types, all differing slightly from each other, can amount to tens of thousands, or millions in a given organism. Such a wide variety increases the odds of having a sub-type that recognises one of the many pathogens an organism may encounter. Too few sub-types and the pathogen can avoid the immune system, unchallenged, leading to disease.

Contents

Development

Lymphocytes generate the immune repertoire by recombining the genes encoding immunoglobulins and T cell receptors through V(D)J recombination. Although there are only a few of these genes, all their possible combinations can result in a wide variety of immune repertoire proteins. Through selection, cells with autoreactive proteins (and thus may cause autoimmunity) are removed, while cells that may actually detect an invading organism are kept. The immune repertoire is affected by several factors:

Size

Due to technical difficulties, measuring the immune repertoire was seldom attempted. Estimates depend on the precise type or 'compartment' of immune cells and the protein studied, but the expected billions of combinations may be an over-estimation. The genetic spatio-temporal rule governing the TCR locus rearrangements imply that V(D)J rearrangements are not random, hence resulting in a smaller V(D)J diversity. [2]

Future developments

Next generation sequencing may have a large impact. [5] This can obtain thousands of DNA sequences, from different genes, quickly, at the same time, relatively cheaply. Thus it may be possible, to take a large sample of cells from someones immune system, and look quickly at the range of sub-types present in the sample. The ability to obtain data quickly from tens or hundreds of thousands of cells, one cell at a time, should provide a good idea, of the size of the person's immune repertoire. These large-scale adaptive immune receptor repertoire sequencing (AIRR-seq) data require specialized bioinformatics pipelines to be analyzed effectively. [6] Many computational tools are being developed for this purpose, including:

The AIRR Community is community-driven organization that is organizing and coordinating stakeholders in the use of next-generation sequencing technologies to study immune repertoires. [11] In 2017, the AIRR Community published recommendations for a minimal set of metadata that should be used to describe an AIRR-seq data set when published and deposited in a public repository. [12]

See also

Related Research Articles

<span class="mw-page-title-main">T cell</span> White blood cells of the immune system

T cells are one of the important types of white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell surface.

<span class="mw-page-title-main">Cytotoxic T cell</span> T cell that kills infected, damaged or cancerous cells

A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pathogens (such as viruses or bacteria), or cells that are damaged in other ways.

<span class="mw-page-title-main">Major histocompatibility complex</span> Cell surface proteins, part of the acquired immune system

The major histocompatibility complex (MHC) is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system. These cell surface proteins are called MHC molecules.

<span class="mw-page-title-main">Adaptive immune system</span> Subsystem of the immune system

The adaptive immune system, also known as the acquired immune system, or specific immune system is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system is one of the two main immunity strategies found in vertebrates.

<span class="mw-page-title-main">CD4</span> Marker on immune cells

In molecular biology, CD4 is a glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). CD4 is found on the surface of immune cells such as T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984. In humans, the CD4 protein is encoded by the CD4 gene.

CD8 is a transmembrane glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). Along with the TCR, the CD8 co-receptor plays a role in T cell signaling and aiding with cytotoxic T cell-antigen interactions.

V(D)J recombination is the mechanism of somatic recombination that occurs only in developing lymphocytes during the early stages of T and B cell maturation. It results in the highly diverse repertoire of antibodies/immunoglobulins and T cell receptors (TCRs) found in B cells and T cells, respectively. The process is a defining feature of the adaptive immune system.

Memory T cells are a subset of T lymphocytes that might have some of the same functions as memory B cells. Their lineage is unclear.

<span class="mw-page-title-main">Immunological synapse</span> Interface between lymphocyte and target cell

In immunology, an immunological synapse is the interface between an antigen-presenting cell or target cell and a lymphocyte such as a T/B cell or Natural Killer cell. The interface was originally named after the neuronal synapse, with which it shares the main structural pattern. An immunological synapse consists of molecules involved in T cell activation, which compose typical patterns—activation clusters. Immunological synapses are the subject of much ongoing research.

A thymocyte is an immune cell present in the thymus, before it undergoes transformation into a T cell. Thymocytes are produced as stem cells in the bone marrow and reach the thymus via the blood.

Allelic exclusion is a process by which only one allele of a gene is expressed while the other allele is silenced. This phenomenon is most notable for playing a role in the development of B lymphocytes, where allelic exclusion allows for each mature B lymphocyte to express only one type of immunoglobulin. This subsequently results in each B lymphocyte being able to recognize only one antigen. This is significant as the co-expression of both alleles in B lymphocytes is associated with autoimmunity and the production of autoantibodies.

MHC-restricted antigen recognition, or MHC restriction, refers to the fact that a T cell can interact with a self-major histocompatibility complex molecule and a foreign peptide bound to it, but will only respond to the antigen when it is bound to a particular MHC molecule.

Large granular lymphocytic (LGL) leukemia is a chronic lymphoproliferative disorder that exhibits an unexplained, chronic elevation in large granular lymphocytes (LGLs) in the peripheral blood.

<span class="mw-page-title-main">Programmed cell death protein 1</span> Mammalian protein found in Homo sapiens

Programmed cell death protein 1(PD-1),. PD-1 is a protein encoded in humans by the PDCD1 gene. PD-1 is a cell surface receptor on T cells and B cells that has a role in regulating the immune system's response to the cells of the human body by down-regulating the immune system and promoting self-tolerance by suppressing T cell inflammatory activity. This prevents autoimmune diseases, but it can also prevent the immune system from killing cancer cells.

<span class="mw-page-title-main">Junctional diversity</span> DNA sequence variations introduced in recombination

Junctional diversity describes the DNA sequence variations introduced by the improper joining of gene segments during the process of V(D)J recombination. This process of V(D)J recombination has vital roles for the vertebrate immune system, as it is able to generate a huge repertoire of different T-cell receptor (TCR) and immunoglobulin molecules required for pathogen antigen recognition by T-cells and B cells, respectively.

T-cell receptor alpha locus is a protein that in humans is encoded by the TRA gene, also known as TCRA or TRA@. It contributes the alpha chain to the larger TCR protein.

Adoptive cell transfer (ACT) is the transfer of cells into a patient. The cells may have originated from the patient or from another individual. The cells are most commonly derived from the immune system with the goal of improving immune functionality and characteristics. In autologous cancer immunotherapy, T cells are extracted from the patient, genetically modified and cultured in vitro and returned to the same patient. Comparatively, allogeneic therapies involve cells isolated and expanded from a donor separate from the patient receiving the cells.

T-cell receptor revision is a process in the peripheral immune system which is used by mature T cells to alter their original antigenic specificity based on rearranged T cell receptors (TCR). This process can lead either to continuous appearance of potentially self-reactive T cells in the body, not controlled by the central tolerance mechanism in the thymus or better eliminate such self-reactive T cells on the other hand and thus contributing to peripheral tolerance - the extent of each has not been completely understood yet. This process occurs during follicular helper T cell formation in lymph node germinal centers.

<span class="mw-page-title-main">CD28 family receptor</span> Group of regulatory cell surface receptors

CD28 family receptors are a group of regulatory cell surface receptors expressed on immune cells. The CD28 family in turn is a subgroup of the immunoglobulin superfamily.

TCR-Seq is a method used to identify and track specific T cells and their clones... TCR-Seq utilizes the unique nature of a T-cell receptor (TCR) as a ready-made molecular barcode. This technology can apply to both single cell sequencing technologies and high throughput screens

References

  1. Blackman, MA; Woodland, DL (2011). "The narrowing of the CD8 T cell repertoire in old age". Current Opinion in Immunology. 23 (4): 537–42. doi:10.1016/j.coi.2011.05.005. PMC   3163762 . PMID   21652194.
  2. Pasqual, N; Gallagher, M; Aude-Garcia, C; Loiodice, M; Thuderoz, F; Demongeot, J; Ceredig, R; Marche, PN; Jouvin-Marche, E (2002). "Quantitative and qualitative changes in V-J alpha rearrangements during mouse thymocytes differentiation: implication for a limited T cell receptor alpha chain repertoire". J. Exp. Med. 196 (9): 1163–73. doi:10.1084/jem.20021074. PMC   2194109 . PMID   12417627.
  3. Dare, R; Sykes, PJ; Morley, AA; Brisco, MJ (2006). "Effect of age on the repertoire of cytotoxic memory (CD8+CD45RO+) T cells in peripheral blood: The use of rearranged T cell receptor gamma genes as clonal markers". Journal of Immunological Methods. 308 (1–2): 1–12. doi:10.1016/j.jim.2005.08.016. PMID   16325196.
  4. Arstila, TP; Casrouge, A; Baron, V; Even, J; Kanellopoulos, J; Kourilsky, P (1999). "A direct estimate of the human alphabeta T cell receptor diversity". Science. 286 (5441): 958–61. doi: 10.1126/science.286.5441.958 . PMID   10542151.
  5. Khan TA, Friedensohn S, de Vries AR, Straszewski J, Ruscheweyh HJ, Reddy ST (2016). "Accurate and predictive antibody repertoire profiling by molecular amplification fingerprinting". Sci. Adv. 2 (3): e1501371. Bibcode:2016SciA....2E1371K. doi:10.1126/sciadv.1501371. PMC   4795664 . PMID   26998518.
  6. Yaari, Gur; Kleinstein, Steven H. (2015-11-20). "Practical guidelines for B-cell receptor repertoire sequencing analysis". Genome Medicine. 7: 121. doi: 10.1186/s13073-015-0243-2 . ISSN   1756-994X. PMC   4654805 . PMID   26589402.
  7. Bolotin, Dmitry; Poslavsky, Stanislav; Mitrophanov, Igor; Shugay, Mikhail; Mamedov, Ilgar; Putintseva, Ekaterina; Chudakov, Dmitriy (2015-04-29). "MiXCR: software for comprehensive adaptive immunity profiling". Nature Methods. 12 (5): 380–381. doi:10.1038/nmeth.3364 . Retrieved 2023-04-30.
  8. Heiden, Vander; A, Jason; Yaari, Gur; Uduman, Mohamed; Stern, Joel N. H.; O’Connor, Kevin C.; Hafler, David A.; Vigneault, Francois; Kleinstein, Steven H. (2014-07-01). "pRESTO: a toolkit for processing high-throughput sequencing raw reads of lymphocyte receptor repertoires". Bioinformatics. 30 (13): 1930–1932. doi:10.1093/bioinformatics/btu138. ISSN   1367-4803. PMC   4071206 . PMID   24618469.
  9. Gupta, Namita T.; Heiden, Vander; A, Jason; Uduman, Mohamed; Gadala-Maria, Daniel; Yaari, Gur; Kleinstein, Steven H. (2015-10-15). "Change-O: a toolkit for analyzing large-scale B cell immunoglobulin repertoire sequencing data". Bioinformatics. 31 (20): 3356–3358. doi:10.1093/bioinformatics/btv359. ISSN   1367-4803. PMC   4793929 . PMID   26069265.
  10. Zheng, G; Terry, J; Belgrader, P (2017-01-16). "Massively parallel digital transcriptional profiling of single cells". Nature Communications. 8: 14049. doi:10.1038/ncomms14049. PMC   5241818 . PMID   28091601.
  11. Breden, Felix; Prak, Luning; T, Eline; Peters, Bjoern; Rubelt, Florian; Schramm, Chaim A.; Busse, Christian E.; Heiden, Vander; A, Jason (2017). "Reproducibility and Reuse of Adaptive Immune Receptor Repertoire Data". Frontiers in Immunology. 8: 1418. doi: 10.3389/fimmu.2017.01418 . ISSN   1664-3224. PMC   5671925 . PMID   29163494.
  12. Rubelt, Florian; Busse, Christian E; Bukhari, Syed Ahmad Chan; Bürckert, Jean-Philippe; Mariotti-Ferrandiz, Encarnita; Cowell, Lindsay G; Watson, Corey T; Marthandan, Nishanth; Faison, William J (2017-11-16). "Adaptive Immune Receptor Repertoire Community recommendations for sharing immune-repertoire sequencing data". Nature Immunology. 18 (12): 1274–1278. doi:10.1038/ni.3873. PMC   5790180 . PMID   29144493.