Co-stimulation

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Co-stimulation is a secondary signal which immune cells rely on to activate an immune response in the presence of an antigen-presenting cell. [1] In the case of T cells, two stimuli are required to fully activate their immune response. During the activation of lymphocytes, co-stimulation is often crucial to the development of an effective immune response. Co-stimulation is required in addition to the antigen-specific signal from their antigen receptors.

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T cell co-stimulation

T cells require two signals to become fully activated. A first signal, which is antigen-specific, is provided through the T cell receptor (TCR) which interacts with peptide-MHC molecules on the membrane of an antigen presenting cell (APC). A second signal, the co-stimulatory signal, is antigen nonspecific and is provided by the interaction between co-stimulatory molecules expressed on the membrane of the APC and the T cell. This interaction promotes and enhances the TCR signaling, but can also be bi-directional. [2] The co-stimulatory signal is necessary for T cell proliferation, differentiation and survival. Activation of T cells without co-stimulation may lead to the unresponsiveness of the T cell (also called anergy), apoptosis or the acquisition of the immune tolerance.[ citation needed ]

The counterpart of the co-stimulatory signal is a (co-)inhibitory signal, where inhibitory molecules interact with different signaling pathways in order to arrest T cell activation. [2] Mostly known inhibitory molecules are CTLA4 and PD1, used in cancer immunotherapy. [2]

In T cell biology there are several co-stimulatory molecules from different protein families. Mostly studied are those belonging to Immunoglobulin super-family (IgSF) (such as CD28, B7, ICOS, CD226 or CRTAM) and TNF receptor super-family (TNFRSF) (such as 41-BB, OX40, CD27, GITR, HVEM, CD40, BAFFR, BAFF and others). Additionally, some co-stimulatory molecules belong to TIM family, CD2/SLAM family or BTN/BTN-like family. [2]

The surface expression of different co-stimulatory molecules is regulated on a transcriptional and post-transcriptional level, but also by endocytosis. [2] The dynamics of the receptor expression usually depends on the cell state. Some molecules are permanently expressed on non-stimulated cells, such as CD28, [3] others only after TCR triggering, for example 41-BB or CD27. [2] [4]

Mechanism of function

Generally, the mechanism of function of co-stimulatory molecules is based on the overlap of their signaling pathway with the primary (TCR) signal and the induction of other, distal pathways often using different routes, leading to the enhancement of TCR signal and expression of effector genes. [2] Additionally, co-stimulatory signaling can also have a unique outcome. [3]

The example of IgSF molecule is one of the most important co-stimulatory molecules expressed on T cells, CD28, which interacts predominantly with CD80 (B7.1) and CD86 (B7.2), but also with B7-H2 (ICOS-L) in humans, present on the membrane of activated APCs. It is constitutively localized, among other important T cell signaling molecules, in the central SMAC (supramolecular activation complex) of the immunological synapse. [3] Its signaling is involved in the recruitment of protein kinase C θ (PKCθ), Ras GEF and Ras GRP to the synapse. [3] [2] Moreover, it induces the activity of NFAT and NFκB transcription factors through interaction with lymphocyte cell-specific protein-tyrosine kinase (LCK) and GRB2 and/or activation of phopshoinositol-3-Kinase (PI3K) resulting in Akt kinase activation, promoting T cell proliferation and IL-2 production. [2] [3] Additionally, it's involved in other biochemical functions of the cell, including T cell metabolism, post-translational protein modifications or cytoskeletal remodeling. [3]

Another costimulatory receptor expressed on T cells is ICOS ( Inducible Costimulator), which interacts with ICOS-L expressed mainly on the APCs. This receptor is genetically closely related to CD28 but cannot substitute for its function. [2] [5] Among many similarities with CD28, it also induces Akt activity through PI3K activation and promotes proliferation. [2] [5] However, there are differences in these pathways, which contribute to the disparity between CD28 and ICOS signaling. [2] [5]

Signaling through co-stimulatory molecules from TNFRSF often involves the interaction with TRAF adaptor proteins to enhance T cell stimulation. [6] For instance, 41-BB (CD137; TNFRSF9) is a signaling molecule expressed mainly on T cells, but also on NK cells. Due to extracellular galectin 9 binding, 41-BB complexes are kept preassembled on the membrane. [4] It interacts with TRAF1 and TRAF2 adaptor proteins, which are involved in pathway eventually leading to NFκB translocation to the nucleus, as well as MAPK/ERK pathway. [4]

OX40 (CD134; TNFRSF4) is another co-stimulatory molecule expressed after T cell activation, but in the later timepoints, since it inhibits apoptosis and increases survival rate several days after the stimulation. [7]

Co-stimulation in different T cell types

CD28 is important practically for all T cell types, but some other co-stimulatory molecules are expressed in some cell types more than in others.

CD2 was shown to prime naive T cells (TN) even without CD28 or TCR. [2] Also, CD27 is a receptor constitutively expressed on TN (its expression is downregulated upon TCR stimulation) and enhances T cell proliferation. [8]

The differentiation of T helper cells (TH) into different subsets also partially depends on their co-stimulatory molecules. TIM1, TIM4, ICOS, CD3 or DR3 and several molecules from the SLAM family were shown to induce polarization towards TH2. [2] [5] In contrast, CD27 and HVEM promote TH1 polarization. [2] OX40 and ICOS expression was linked to T folicular helper (TFH) differentiation and maintenance. [7] Regulatory T cells (TREG) need CD28 signal for their generation and ICOS signal for their peripheral maintenance and survival. In contrast, HVEM, GITR and CD30 are suppressing their activity. [2] [3] [5]

Effector T cells are mainly regulated by TNFRSF molecules, such as 41-BB, CD27, OX40, DR3 or GITR, which enhance their proliferation and survival. [2]

Memory T cells TM were also shown to necessitate co-stimulatory signals. Apart from CD28; ICOS, 41-BB, OX40, TIM3, CD30, BTLA or CD27 were also shown to play role in the proper formation and later signaling of TM. [2] [9]

B cell co-stimulation

B cell binds antigens with its BCR (a membrane-bound antibody), which transfers intracellular signals to the B cell as well as inducing the B cell to engulf the antigen, process it, and present it on the MHC II molecules. The latter case induces recognition by antigen-specific Th2 cells or Tfh cells, leading to activation of the B cell through binding of TCR to the MHC-antigen complex. It is followed by synthesis and presentation of CD40L (CD154) on the Th2 cell, which binds to CD40 on the B cell, thus the Th2 cell can co-stimulate the B cell. [10] Without this co-stimulation the B cell cannot proliferate further. [11]

Co-stimulation for B cells is provided alternatively by complement receptors. Microbes may activate the complement system directly and complement component C3b bind to microbes. After C3b is degraded into a fragment iC3b (inactive derivative of C3b), then cleaved to C3dg, and finally to C3d, which continue to bind to microbial surface, B cells express complement receptor CR2 (CD21) to bind to iC3b, C3dg, or C3d. [12] This additional binding makes the B cells 100- to 10,000-fold more sensitive to antigen. [13] CR2 on mature B cells forms a complex with CD19 and CD81. This complex is called the B cell coreceptor complex for such sensitivity enhancement to the antigen. [14]

Applications

Abatacept (Orencia) is a T cell co-stimulation modulator approved for the treatment of rheumatoid arthritis. The cytokines secreted by activated T cells are thought to both initiate and propagate the immunologically driven inflammation associated with rheumatoid arthritis. Orencia, a soluble fusion protein, works by altering the co-stimulatory signal required for full T-cell activation. Belatacept is another novel molecule which is being tested as an anti-rejection medication for use in renal transplantation.

A new co-stimulatory superagonistic drug, TGN1412, was the subject of a clinical trial at Northwick Park Hospital, London. The trial became surrounded in controversy as the six volunteers became seriously ill within minutes of being given the drug.

In essence, the co-stimulatory molecules function as "flashing red lights" that interact with the T cell, communicating that the material being presented by the dendritic cell material indicates danger. Dendritic cells displaying co-stimulatory molecules while presenting antigen are able to activate T cells. In contrast, T cells that recognize antigen presented by a dendritic cell not displaying co-stimulatory molecules are generally driven to apoptosis, or may become unresponsive to future encounters with the antigen.

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">T helper cell</span> Type of immune cell

The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4+ cells are mature Th cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4+ cells determines susceptibility to a broad class of autoimmune diseases.

<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">Antigen-presenting cell</span> Cell that displays antigen bound by MHC proteins on its surface

An antigen-presenting cell (APC) or accessory cell is a cell that displays antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes using their T cell receptors (TCRs). APCs process antigens and present them to T-cells.

<span class="mw-page-title-main">T-cell receptor</span> Protein complex on the surface of T cells that recognises antigens

The T-cell receptor (TCR) is a protein complex found on the surface of T cells, or T lymphocytes, that is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. The binding between TCR and antigen peptides is of relatively low affinity and is degenerate: that is, many TCRs recognize the same antigen peptide and many antigen peptides are recognized by the same TCR.

<span class="mw-page-title-main">Fc receptor</span> Surface protein important to the immune system

In immunology, an Fc receptor is a protein found on the surface of certain cells – including, among others, B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils, human platelets, and mast cells – that contribute to the protective functions of the immune system. Its name is derived from its binding specificity for a part of an antibody known as the Fc region. Fc receptors bind to antibodies that are attached to infected cells or invading pathogens. Their activity stimulates phagocytic or cytotoxic cells to destroy microbes, or infected cells by antibody-mediated phagocytosis or antibody-dependent cell-mediated cytotoxicity. Some viruses such as flaviviruses use Fc receptors to help them infect cells, by a mechanism known as antibody-dependent enhancement of infection.

<span class="mw-page-title-main">CD28</span> Mammalian protein found in humans

CD28 is one of the proteins expressed on T cells that provide co-stimulatory signals required for T cell activation and survival. T cell stimulation through CD28 in addition to the T-cell receptor (TCR) can provide a potent signal for the production of various interleukins.

Nuclear factor of activated T-cells (NFAT) is a family of transcription factors shown to be important in immune response. One or more members of the NFAT family is expressed in most cells of the immune system. NFAT is also involved in the development of cardiac, skeletal muscle, and nervous systems. NFAT was first discovered as an activator for the transcription of IL-2 in T cells but has since been found to play an important role in regulating many more body systems. NFAT transcription factors are involved in many normal body processes as well as in development of several diseases, such as inflammatory bowel diseases and several types of cancer. NFAT is also being investigated as a drug target for several different disorders.

<span class="mw-page-title-main">CD278</span> Protein-coding gene in the species Homo sapiens

Inducible T-cell costimulator is an immune checkpoint protein that in humans is encoded by the ICOS gene. The protein belongs to the CD28 and CTLA-4 cell-surface receptor family. These are proteins expressed on the surface of immune cells that mediate signalling between them. A surface protein, the ligand, binds specifically to its receptor on another cell, leading to a signalling cascade in that cell.

<span class="mw-page-title-main">CD80</span> Mammalian protein found in Homo sapiens

The Cluster of differentiation 80 is a B7, type I membrane protein in the immunoglobulin superfamily, with an extracellular immunoglobulin constant-like domain and a variable-like domain required for receptor binding. It is closely related to CD86, another B7 protein (B7-2), and often works in tandem. Both CD80 and CD86 interact with costimulatory receptors CD28, CTLA-4 (CD152) and the p75 neurotrophin receptor.

<span class="mw-page-title-main">CD86</span> Mammalian protein found in Homo sapiens

Cluster of Differentiation 86 is a protein constitutively expressed on dendritic cells, Langerhans cells, macrophages, B-cells, and on other antigen-presenting cells. Along with CD80, CD86 provides costimulatory signals necessary for T cell activation and survival. Depending on the ligand bound, CD86 can signal for self-regulation and cell-cell association, or for attenuation of regulation and cell-cell disassociation.

<span class="mw-page-title-main">CD134</span> Protein-coding gene in humans

Tumor necrosis factor receptor superfamily, member 4 (TNFRSF4), also known as CD134 and OX40 receptor, is a member of the TNFR-superfamily of receptors which is not constitutively expressed on resting naïve T cells, unlike CD28. OX40 is a secondary co-stimulatory immune checkpoint molecule, expressed after 24 to 72 hours following activation; its ligand, OX40L, is also not expressed on resting antigen presenting cells, but is following their activation. Expression of OX40 is dependent on full activation of the T cell; without CD28, expression of OX40 is delayed and of fourfold lower levels.

<span class="mw-page-title-main">C3b</span>

C3b is the larger of two elements formed by the cleavage of complement component 3, and is considered an important part of the innate immune system. C3b is potent in opsonization: tagging pathogens, immune complexes (antigen-antibody), and apoptotic cells for phagocytosis. Additionally, C3b plays a role in forming a C3 convertase when bound to Factor B, or a C5 convertase when bound to C4b and C2b or when an additional C3b molecule binds to the C3bBb complex.

<span class="mw-page-title-main">CD137</span> Member of the tumor necrosis factor (TNF) receptor family

CD137, a member of the tumor necrosis factor (TNF) receptor family, is a type 1 transmembrane protein, expressed on surfaces of leukocytes and non-immune cells. Its alternative names are tumor necrosis factor receptor superfamily member 9 (TNFRSF9), 4-1BB, and induced by lymphocyte activation (ILA). It is of interest to immunologists as a co-stimulatory immune checkpoint molecule, and as a potential target in cancer immunotherapy.

<span class="mw-page-title-main">CD27</span> Member of the tumor necrosis factor receptor superfamily.

CD27 is a member of the tumor necrosis factor receptor superfamily. It is currently of interest to immunologists as a co-stimulatory immune checkpoint molecule, and is the target of an anti-cancer drug in clinical trials.

<span class="mw-page-title-main">ICOSLG</span> Protein-coding gene in the species Homo sapiens

ICOS ligand is a protein that in humans is encoded by the ICOSLG gene located at chromosome 21. ICOSLG has also been designated as CD275.

<span class="mw-page-title-main">TNFRSF18</span> Protein-coding gene in the species Homo sapiens

Tumor necrosis factor receptor superfamily member 18 (TNFRSF18), also known as glucocorticoid-induced TNFR-related protein (GITR) or CD357. GITR is encoded and tnfrsf18 gene at chromosome 4 in mice. GITR is type I transmembrane protein and is described in 4 different isoforms. GITR human orthologue, also called activation-inducible TNFR family receptor (AITR), is encoded by the TNFRSF18 gene at chromosome 1.

The following outline is provided as an overview of and topical guide to immunology:

<span class="mw-page-title-main">Immune checkpoint</span> Regulators of the immune system

Immune checkpoints are regulators of the immune system. These pathways are crucial for self-tolerance, which prevents the immune system from attacking cells indiscriminately. However, some cancers can protect themselves from attack by stimulating immune checkpoint targets.

<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.

References

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  4. 1 2 3 Sanchez-Paulete, Alfonso R.; Labiano, Sara; Rodriguez-Ruiz, Maria E.; Azpilikueta, Arantza; Etxeberria, Iñaki; Bolaños, Elixabet; Lang, Valérie; Rodriguez, Manuel; Aznar, M. Angela; Jure-Kunkel, Maria; Melero, Ignacio (March 2016). "Deciphering CD137 (4-1BB) signaling in T-cell costimulation for translation into successful cancer immunotherapy". European Journal of Immunology. 46 (3): 513–522. doi: 10.1002/eji.201445388 . PMID   26773716. S2CID   2200367.
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  6. ↑ Ward-Kavanagh, Lindsay K.; Lin, Wai Wai; Šedý, John R.; Ware, Carl F. (2016-05-17). "The TNF Receptor Superfamily in Co-stimulating and Co-inhibitory Responses". Immunity. 44 (5): 1005–1019. doi:10.1016/j.immuni.2016.04.019. ISSN   1074-7613. PMC   4882112 . PMID   27192566.
  7. 1 2 Fu, NanNan; Xie, Fang; Sun, ZhongWen; Wang, Qin (2021). "The OX40/OX40L Axis Regulates T Follicular Helper Cell Differentiation: Implications for Autoimmune Diseases". Frontiers in Immunology. 12: 670637. doi: 10.3389/fimmu.2021.670637 . ISSN   1664-3224. PMC   8256170 . PMID   34234777.
  8. ↑ Lutfi, Forat; Wu, Long; Sunshine, Sarah; Cao, Xuefang (2021-09-22). "Targeting the CD27-CD70 Pathway to Improve Outcomes in Both Checkpoint Immunotherapy and Allogeneic Hematopoietic Cell Transplantation". Frontiers in Immunology. 12: 715909. doi: 10.3389/fimmu.2021.715909 . ISSN   1664-3224. PMC   8493876 . PMID   34630390.
  9. ↑ Liu, Qingjun; Sun, Zhongjie; Chen, Ligong (2020-08-01). "Memory T cells: strategies for optimizing tumor immunotherapy". Protein & Cell. 11 (8): 549–564. doi:10.1007/s13238-020-00707-9. ISSN   1674-8018. PMC   7381543 . PMID   32221812.
  10. ↑ Janeway CA, Travers P, Walport M, Shlomchik M (2001). Immunobiology 5 : The Immune System in Health and Disease, 5th ed. New York: Garland Pub., ISBN   0-8153-3642-X
  11. ↑ Noelle, R. J.; Roy, M.; Shepherd, D. M.; Stamenkovic, I.; Ledbetter, J. A.; Aruffo, A. (1992). "A 39-kDa protein on activated helper T cells binds CD40 and transduces the signal for cognate activation of B cells". Proceedings of the National Academy of Sciences of the United States of America. 89 (14): 6550–6554. Bibcode:1992PNAS...89.6550N. doi: 10.1073/pnas.89.14.6550 . PMC   49539 . PMID   1378631.
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  14. ↑ Abbas AK, Lichtman AH (2003). Cellular and Molecular Immunology, 5th ed. Philadelphia: Saunders, ISBN   0-7216-0008-5.
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