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World J Immunol. Jan 24, 2022; 12(1): 1-8
Published online Jan 24, 2022. doi: 10.5411/wji.v12.i1.1
Historical evolution, overview, and therapeutic manipulation of co-stimulatory molecules
Henry Velazquez-Soto, Fernanda Real, Maria C Jiménez-Martínez, Department of Immunology and Research Unit, Institute of Ophthalmology “Conde de Valenciana”, Mexico City 06800, Mexico
Maria C Jiménez-Martínez, Department of Biochemistry, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico
ORCID number: Henry Velazquez-Soto (0000-0002-7405-4875); Fernanda Real (0000-0001-9839-0788); Maria C Jiménez-Martínez (0000-0003-3982-9097).
Author contributions: Velazquez-Soto H drafted the paper and designed the outline; Real F prepared the figures and tables, and reviewed the paper; Jiménez-Martínez MC reviewed the paper, figures and tables, coordinated the paper’s preparation, and approved the final version.
Supported by Institute of Ophthalmology “Fundación Conde de Valenciana”; Velazquez-Soto H received fellowship 294674 from CONACYT during his doctoral studies in Programa de Doctorado en Ciencias Médicas, Odontológicas y de la Salud (Farmacología Clínica), Universidad Nacional Autónoma de México (UNAM); Real F with CVU 917729, recieved fellowship from CONACYT during his master studies in Programa de Maestría en Ciencias Médicas, Odontológicas y de la Salud (Farmacología Clínica), Universidad Nacional Autónoma de México (UNAM).
Conflict-of-interest statement: The authors declare that they have no conflicting interests.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Maria C Jiménez-Martínez, MD, PhD, Chief Doctor, Department of Immunology and Research Unit, Institute of Ophthalmology “Conde de Valenciana”, Chimalpopoca 14, Col. Obrera, Del. Cuauhtemoc, Mexico City 06800, Mexico.
Received: April 28, 2021
Peer-review started: April 28, 2021
First decision: July 8, 2021
Revised: August 5, 2021
Accepted: December 22, 2021
Article in press: December 22, 2021
Published online: January 24, 2022


Co-stimulatory molecules are key mediators in the regulation of immune responses and knowledge of its different families, structure, and functions has improved in recent decades. Understanding the role of co-stimulatory molecules in pathological processes has allowed the development of strategies to modulate cellular functions. Currently, modulation of co-stimulatory and co-inhibitory molecules has been applied in clinical applications as therapeutic targets in diseases and promising results have been achieved.

Key Words: Co-stimulatory molecules, Immune modulation, Monoclonal antibodies, Biological therapy, Autoimmune diseases, Oncological diseases

Core Tip: Several reviews of co-stimulatory molecules have been published, however, this review summarizes the historical aspects, the cellular and molecular mechanisms of the different families of costimulatory molecules implied in processes of health and disease. All of this knowledge has been applied to develop different drugs targeting costimulatory molecules in different diseases like cancer and autoimmune diseases.


Regulation of the immune response is a crucial process in the initiation and control of inflammatory phenomena. Various mechanisms capable of regulating T cell activation have been described. Co-stimulatory molecules were initially described as accessory signals present in antigen-presenting cells (APCs) that interacted with T cells during the immunological synapse[1]. They comprise a diversity of glycoproteins expressed in the membrane of APCs, and they interact with other glycoproteins that function as their receptors on T cells, modulating in a positive or negative way the activation, proliferation, differentiation, and function of T cells[2]. In recent decades, advances in the knowledge of co-stimulatory molecules and the development of biological drugs allowed a therapeutical targeting of co-stimulatory molecules in distinct diseases[3].


A two-signal model of T cell activation was first proposed in the second half of the 1960s. The two signals were antigen recognition by an antigen receptor and the interaction with co-stimulatory molecules. Although the mechanisms were not known, the model proposed that in the absence of a second signal or "co-stimulation," the T cell would enter a state of paralysis or inactivation[4,5]. By the second half of the 1980s, a series of investigations had experimentally demonstrated the existence of co-stimulatory molecules and their participation in T cell activation[6-9]. The findings resulted in the description of a diversity of molecules and the investigation of their function in different disease models, which led to therapeutic applications. One example is the 2018 Nobel Prize in Physiology and Medicine, awarded to Tsuku Honjo and James P Alisson, for their contributions to the discovery of cytotoxic T lymphocyte–associated antigen (CTLA)-4 and programmed death (PD)-1 protein and the development of methods of molecular blockade for the treatment of oncological diseases[10-12].


APCs are part of the innate immune system and act as an interface between antigen recognition and the adaptive response of T cells during antigen presentation[3]. Activation of T cells requires the appropriate activation and integration of three signals. The first signal is the antigen, which is presented in the context of the major histocompatibility complex, and its recognition by the T cell receptor (TCR). The first signal is not sufficient to activate T cells. Activation continues with a second signal that involves the participation of surface molecules expressed on dendritic cells that interact with their respective receptors on the T cell. The third signal involves the production of cytokines, which not only favor the activation state but also promote the polarization of T cells into their various helper/cytotoxic subpopulations[3,13] (Figure 1). In that dynamic microenvironment, the spatiotemporal expression of various co-stimulatory molecules on dendritic cells and T cells, as part of the second signal, is the key to regulating T cell activation, inhibition, survival, and polarization.

Figure 1
Figure 1 Overview of antigen presentation and the three-signal model. The three-signal model proposes: (1) Antigen presentation to the T cell receptor by the major histocompatibility complex; (2) Interaction of co-stimulatory molecules with their receptors; and (3) Cytokine production and recognition by the cytokine receptors of T cells. DAMPs: Damage-associated molecular patterns; PAMPS; Pathogen-associated molecular patterns; PD1: Programmed death-1; PDL1: Programmed death ligand 1; PRR: Pattern recognition receptor.
Activating and inhibitory signals

Co-stimulatory molecules are transmembrane glycoproteins that induce activation or inhibition cascades that enhance or diminish TCR signaling[14,15]. Stimulatory, or activating signals (co-stimulation by CD28 or CD40), lead to the production of growth factors, cell expansion, and survival. Inhibitory signals (co-inhibition by PD1 or CTL-4) attenuate TCR-induced signals, resulting in decreased cell activation, inhibition of growth factor production, inhibition of cell cycle progression, and in some cases, promotion of cell death[14].

Families of co-stimulatory molecules

Co-stimulatory molecules are divided into two main families by their molecular structure. The first (Table 1) is the immunoglobulin superfamily which includes CD226, the CD2/signaling lymphocytic activation molecule family, T cell immunoglobulin and mucin (TIM) family, butyrophilin (BTN) family, and leukocyte-associated immunoglobulin-like receptor (LAIR) family. Because of its historical relevance, the most studied is the B7 family, which includes CD80, CD86, and its receptor CD28. The second (Table 2) is the tumor necrosis factor superfamily (TNFR SF), which includes three subfamilies, the divergent type (OX-40, CD27, glucocorticoid-induced TNFR-related protein), the S-type (CD267), and the conventional type [FAS, herpes virus entry mediator, receptor activator of nuclear factor kappa-B (RANK), and CD40]. CD40 and its ligand CD40L are the most investigated co-stimulation molecules of the TNFR SF[3].

Table 1 Immunoglobulin super family co-stimulatory molecules.
IgSF co-stimulatory molecules
Cells expressing the receptor
Cells expressing the ligand
CD28ActivationConstitutive in T cellsCD80, CD86CD80: Inducible in dendritic cells, monocytes, B and T cells. CD86: Constitutive in dendritic cells, monocytes, B and T cells
ICOS (CD278)ActivationInducible in T, B, and NK cellsICOSLConstitutive in macrophages, dendritic cells, B and T cells
CTLA-4 (CD152)InhibitionInducible in T cellsCD80, CD86CD80: Inducible in dendritic cells, monocytes, B and T cells. CD86: Constitutive in dendritic cells, monocytes, B and T cells
PD-1 (CD279)InhibitionInducible in T, and B cells, macrophagesPD-L1, PD-L2PD-L1: Constitutive in dendritic cells, B and T cells. PD-L2: Inducible in dendritic cells and monocytes
PD-1H (VISTA)InhibitionMonocytes, neutrophils, T cellsUnknownUnknown
BTLA (CD272)InhibitionB and T cellsHVEM, UL144Monocytes, B and T cells
B71 (CD80), B72 (CD86)Activation/InhibitionCD80: Inducible in dendritic cells, monocytes, B and T cells. CD86: Constitutive in dendritic cells, monocytes, B and T cellsCD28, CTLA-4CD28: Constitutive in T cells. CTLA-4: Inducible in T cells
B7H1 (CD274, PDL1)InhibitionConstitutive in dendritic cells, monocytes, B and T cellsPD-1, B71PD-1: Inducible in macrophages, B and T cells. CD80: Inducible in dendritic cells, monocytes, B and T cells
Table 2 Tumor necrosis factor receptor super family co-stimulatory molecules.
TNFR SF co-stimulatory molecules
Cells expressing the receptor
Cells expressing the ligand
OX40 (CD134)ActivationActivated and regulatory T cellsOX40LT cells, macrophages, endothelial cells, vascular smooth muscle cells, dendritic cells, tumor cells
CD27 (TNFR SF7)ActivationT and B cells, NK cellsCD70NK, T and B cells
GITR (CD357)ActivationT cellsGITRLT cells
CD30 (TNFR SF8)ActivationT and B cellsCD30LT cells
HVEM (CD270)ActivationMonocytes, T and B cellsLIGHT, BTLA, CD160, LTα3, HSV1gDMonocytes and APCs
FAS (CD95)ActivationNK and T cellsFASLDendritic cells, NK, T cells, neutrophils
CD40 (TNFR SF5)ActivationAll B-cell lineages except plasma cells, macrophages, activated monocytes, follicular dendritic cells, interdigitating dendritic cells, endothelial cells, fibroblastsCD40LActivated CD4+ T cells, some CD8+ T cells, γδ T cells, basophils, platelets monocytes and mast cells
RANK (CD265)ActivationOsteoclast and dendritic cellsRANKLOsteoblasts, T cells
TACI (CD267)InhibitionB and plasma cellsBAFF, APRILStromal cells, dendritic cells, and macrophages
Co-stimulatory molecules and their study in human disease

The involvement of co-stimulatory molecules in clinical conditions has been explored. Mutations in ICOSL, CD40, or C267 have been associated with immunodeficiencies; increased expression of CD86, CD28, CD27, and CD70 has been reported in autoimmune diseases and allergies[16-23]. Some of the most interesting findings are summarized in Tables 3 and 4.

Table 3 Immunoglobulin super family co-stimulatory molecules studied in various diseases.
CD86Rheumathoid arthritisIncreased expression in B cells[16]
ICOSLCombined immunodeficiencyMutation[17]
CTLA-4Mycosis fungoidesIncreased expression in T cells[18]
CD28TuberculosisDecreased expression in CD8+ and CD4+ T cells[19]
CD28Graves’ diseaseIncreased expression in T cells[20]
Table 4 Tumor necrosis factor superfamily co-stimulatory molecules studied in various diseases.
CD27Lupus erythematosusIncreased expression in plasmablasts[21]
CD70Lupus erythematosusIncreased expression in plasmablasts[21]
CD40Hyper IgM SyndromeMutations[22]
CD30Vernal KeratoconjunctivitisIncreased expression in T cells[23]
CD267Common variable immunodeficiencyMutations[24]
Therapeutic application of co-stimulatory or co-inhibitory molecules

Numerous scientific studies have shown the involvement of co-stimulatory molecules in the regulation of the inflammatory process[3]. Subsequently, both experimental trials in various disease models and preclinical trials have demonstrated promising results achieved by the therapeutic manipulation of these molecules[24,25]. The preclinical results support their application at the clinical level either by inhibiting the function of activating co-stimulatory molecules to promote tolerogenic functions or by inhibiting inhibitory co-stimulatory molecules to promote pro-inflammatory functions.

Blockade of the co-inhibitory molecules PD1 and CTLA-4 by the monoclonal antibodies pembrolizumab, ipilimumab, and nivolumab is a therapeutic indication in cancer treatment, particularly melanoma. On the other hand, therapeutic approaches for autoimmune diseases have exploited the blockade of the co-stimulatory molecules CD80/CD86 by abatacept or CD40 by iscalimab. In both cases, co-stimulatory molecule-targeted therapies have shown promising results[26-32] (Figure 2 and Table 5).

Figure 2
Figure 2 Therapeutical manipulation of co-stimulatory molecules. Biological drugs have been developed to target co-stimulatory molecules and promote or inhibit their functions in distinct diseases. For example, the fusion protein abatacept blocks CD80/CD86 to prevent interaction with CD28; mAb iscalimab blocks CD40, ipilimumab blocks cytotoxic T lymphocyte antigen-4, and pembrolizumab blocks programmed death-1 (PD-1). These strategies have been implemented to modulate co-stimulatory molecule functions in immune and cancer cells. MHC: Major histocompatibility complex; TCR: T cell receptor.
Table 5 Co-stimulatory molecule manipulation in various diseases.
Therapeutic target
Brain metastases melanomaPD-1 and CTLA-4Blockade with mAbs (nivolumab + ipilimumab)55% of treated patients reduced tumor size. 21% showed full response[27]
MelanomaPD-1Blockade with mAbs (pembrolizumab or nivolumab)19% of treated patient reduced tumor size[28]
MelanomaPD-1Blockade with mAbs (pembrolizumab)33% of treated patient reduce size tumor[29]
Rheumatoid arthritisCD80/CD86Blockade with soluble receptor (abatacept)Reduction in the disease index[30]
Psoriatic arthritisCD80/CD86Blockade with soluble receptor (abatacept)Musculoskeletal clinical improving[31]
Sjögren syndromeCD40Blockade with recombinant antibody (CFZ533 or iscalimab)Reduction in the disease index[32]
Kidney graftCD40Blockade with recombinant antibody (CFZ533 or iscalimab)Transplant success rate similar to tacrolimus treatment, but with a lower probability of adverse effects and infections[33]

Challenging limitations need to be overcome before these therapeutical tools are approved for clinical use[33]. Nevertheless, understanding the function and the possibility of therapeutic manipulation of co-stimulatory molecules represents a milestone for immunology and pharmacology. The knowledge gained from the study of co-stimulatory molecules has allowed a deeper understanding of the pathophysiology of many diseases. The therapeutic use of these molecules has been well exploited in autoimmune diseases and oncology, where they serve as effective adjuvants to conventional therapy. However, we should not exclude the potential that these molecules have in many other contexts. They will undoubtedly continue to be an area of great interest for research and drug development.


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