key: cord-0717014-j0t8rjkc
authors: Odales, Josué; Guzman Valle, Jesus; Martínez-Cortés, Fernando; Manoutcharian, Karen
title: Immunogenic properties of immunoglobulin superfamily members within complex biological networks
date: 2020-10-11
journal: Cell Immunol
DOI: 10.1016/j.cellimm.2020.104235
sha: 15d56743bcbed8ca73d9af0d6345392cab353223
doc_id: 717014
cord_uid: j0t8rjkc

Antibodies, T cell receptors and major histocompatibility complex molecules are members of the immunoglobulin superfamily and have pivotal roles in the immune system. The fine interrelation between them regulates several immune functions. Here, we describe lesser-known functions ascribed to these molecules in generating and maintaining immune response. Particularly, we outline the contribution of antibody- and T cell receptor-derived complementarity-determining region neoantigens, antigenized antibodies, as well as major histocompatibility complex class I molecules-derived epitopes to the induction of protective/therapeutic immune responses against pathogens and cancer. We discuss findings of our own and other studies describing protective mechanisms, based on immunogenic properties of immunoglobulin superfamily members, and evaluate the perspectives of application of this class of immunogens in molecular vaccines design.

Idiotypic antibody 

The immunoglobulin (Ig) superfamily is a large functionally diverse group of proteins which bear a common Ig domain, consisting of two anti-parallel β-sheets stabilized with a disulfide bond [1] . Antibodies (Abs), T cell receptors (TCRs) and major histocompatibility complex (MHC) class I or class II molecules are members of Ig superfamily that play critical roles in immune response network [1, 2] .

Since the discovery of the therapeutic potential of serum from animals exposed to attenuated pathogens, more than a century ago, huge progress in the development of Ab-based therapeutics has been made. Many Abs are currently being used to treat several major pathological conditions: cancer, autoimmune, cardiovascular, infectious and neurodegenerative diseases, and the mechanisms of action of Ab treatment has been reviewed elsewhere [3] [4] [5] [6] [7] [8] .

TCR and Ab molecules contain three complementarity-determining regions (CDRs), per variable domain, which are responsible for Ag recognition. CDR3 is the most diverse region, in terms of sequence and length, and is considered the most important in determining the specificity of a given Ab or TCR [9] . B lymphocytes often undergo affinity maturation after initial encounter with Ag, subsequently they produce new, slightly modified Abs with increased affinity. This implies that the Ag-Ab interaction is almost perfect, i.e., the six CDRs of a given Ab would be the "specular image" of the interaction established with a specific Ag. For decades, there has been compelling evidence of CDR-specific T and B lymphocyte activation. This concept is partially based on the proposed Ab network, pioneered by Jerne in 1974 ( Fig. 1 A) , which suggests that one antibody (Ab1) will induce an effective immune response that generates a second Ab (Ab2: Ab2α targeting the region close to Ag-recognizing site of Ab1 proposed to describe the optimal affinity during pMHC-TCR interaction: kineticproofreading and serial triggering models; along with the prediction that there is an upper and lower limit to the half-life during pMHC-TCR complex binding, which narrows the range of optimal affinities leading to T cell activation [2] .

During organ transplantation, determining MHC compatibility between the donorderived organ and recipient is a crucial step to reduce rejection mediated by graftversus-host interaction. Today, the presence of donor-derived HLA-specific Ab and T cell responses are suggested as part of the leading causes of organ rejection [18] .

Preexisting organ-specific Ab responses lead to acute Ab-mediated rejection, even though Ab responses could be elicited any time after organ transplantation;

furthermore, direct or indirect T cell-mediated organ rejection provides other mechanisms that act in conjunction with Ab responses leading to the damage of the transplanted organ or finally, to the patient death [19, 20] , (Fig. 1 B) . Also, autoimmunity, mediated by non-HLA Ab responses following solid organ transplantation, contributes to transplant rejection [21] .

Cancer cells generally present modified versions, or abnormal expression of MHC molecules, as seen through loss of heterozygosity or loss of expression, which are associated with immune editing of tumors, and may contribute to cancer evolution and immune escape [22, 23] . In line with the abovementioned immune mechanisms of organ rejection, and with the potential immunogenicity of MHC molecules ( Fig. 1 B) , we were the first, to our knowledge, to generate cancer vaccine immunogens, based on peptides derived from MHC Qa-2 and H2-K molecules, and to show their protective effects targeting the tumor as a transplanted organ in a mouse model of breast cancer [24] . We have demonstrated significant inhibition of the tumor growth and the reduction of metastatic lesions in the lungs of immunized animals [24] . Therefore, harnessing the immunogenic properties of MHC molecules might provide an entirely new direction to treat cancer.

Furthermore, newly synthetized MHC class I α chains contain signal peptides that do not form part of the mature protein. These signal peptides remain in the endoplasmic reticulum after cleavage from the α chain, but afterwards are processed by proteolytic cleavage via signal peptide peptidase, and their amino-terminal portion is released into the cytosol. The MHC class I-derived signal peptide reenters the normal MHC class I antigen processing and presentation pathway and is finally loaded, specifically, on the non-classical HLA-E molecule whose function is immunosurveillance [25] . This mechanism indirectly evaluates MHC class I protein level translation. The NK and CD8 + T cell CD94/NKG-2A inhibitory and CD94/NKG-2C activating receptors oversee the production of peptide-HLA-E complexes [26, 27] . In addition, inhibitory KIR family receptors on cytotoxic cells directly recognize MHC class I molecules and function by protecting normal non-stressed cells from cytotoxic lysis [28] . Thus, MHC molecules have several immunological functions beyond the immunological synapse with T lymphocytes.

Muromonab-CD3 (OKT-3) was the first anti-human CD3 monoclonal antibody approved for human use by the Food and Drug Administration (FDA) in 1986 [29] . It was used to prevent organ rejection after transplantation by primarily reducing T cell functions. In 86% of patients treated with the murine Ab, human anti-drug antibodies (ADAs) were induced, a phenomenon known as human anti-mouse antibody (HAMA) response [29] .

The ADA response decreases the efficacy of the treatment and induces adverse effects such as hypersensitivity-type reactions [30] . These findings encourage efforts to reduce Ab-related drug immunogenicity in order to develop better and safer drugs. This led to Ab chimerization which is a process where xenogeneic Ig constant regions are replaced by human Ig constant sequences, in this manner Ab-associated immunogenicity is reduced. Rituximab (Rituxan) was the first FDA-approved chimeric Ab in 1997 and is a CD20-specific Ab used to treat several B lymphocyte-related conditions [31] . Unfortunately, an ADA response was also generated against [44, 45] . Importantly, sera obtained from mice immunized with

VELs were able to neutralize half of a Tier-2 HIV-1 reference panel [45] . We also confirmed the anti-Id nature of these Abs by isolation of an Ab-binding peptide motif that resembles the original HIV-1 epitope after screening of immune sera against phage display random peptide libraries [43] . In cancer-related research, we generated For over 30 years, Ab-based therapy has been approved by medical regulatory agencies worldwide and has been used in various clinical settings. Ab-based therapy is widely considered a safe and effective medical treatment; however, adverse effects in patients have been reported [47, 48] . To our knowledge, long-term studies on the undesirable effects of Ab treatment have not been conducted, thus we are most likely ignorant to the consequences of manipulating the immune system. Although several mechanisms of action have been described for this treatment modality, in most cases, these can be reduced to (i) an interaction-blocking agent and/or (ii) a targeted drug with Fc-related immune effector functions. However, other unorthodox therapeutic approaches have also been explored such as anti-idiotype vaccines and intravenous immunoglobulin (IVIG) treatment.

The anti-idiotype vaccine concept is based on the idiotype/anti-idiotype cascade proposed by Jerne ( Fig. 1 A) showed longer median survival time [51] . These results led Vaxira to be the first approved anti-idiotype vaccine, with permission granted in Cuba and Argentina. A phase III clinical trial using Vaxira is currently undergoing (www.clinicaltrials.com).

IVIG is a blood product consisting primarily of a mixture of IgGs from thousands of healthy donors. The main indication for IVIG is in replacement therapy, where low doses (300 mg/kg, every 3 weeks) are administered to patients with immunodeficiencyrelated conditions, with the purpose of providing passive immunity against pathogens [52] . Furthermore, IVIG has immunomodulatory effects at high concentrations (2 g/kg/month), where it has been used for the treatment of autoimmune or inflammatory disorders [53, 54] . Interestingly, positive preliminary data on IVIG therapy in pediatric COVID-19 patients have been reported recently, and its use in other groups of patients is under consideration [55] . The mechanism of action for the immunomodulatory effects are not well established but many Fab-and Fc-dependent mechanisms are presumed to be involved, e.g., Ab neutralization, cytokines, complement molecules, blockade of neonatal Fc receptor and Fc activating receptors [56, 57] . Also, the presence of T cell epitopes for natural regulatory T cells (nTreg) in the primary IgG sequence is presumed to be involved in increasing the nTreg population, concomitant to reduction of the proliferative T cell response [58] . The induction of these nTregs that recognize highly promiscuous MHC class II T-cell epitopes or "Tregitopes" in the Fc fragment of IgG, as a possible mechanism for the immunosuppressive activity of IgG, may have clinical implications; for example, for hemophilia treatment, to avoid immunogenicity and induce immune tolerance, the recombinant factor VIII (rFVIII) and rFIX, fused to the Fc domain of IgG, have been developed as therapeutic agents with longer-lasting circulating half-life [58, 59] .

Regarding TCRs, their αβ protein chains are limited to expression as a membrane anchored complex, not in a soluble form, and are functionally restricted to MHC molecules. For these reasons, the TCR has not been exploited in the biotechnology field as much as Abs. However, based on the similarity in immune functions and structure with the B cell receptor (BCR)/Ab, we could expect similar immunogenic properties to be mirrored by the TCR. Indeed, it has been proven that a Morbillivirus nucleocapsid protein-specific CD8 + T cells, stimulated in vitro, process and present its own TCR-derived peptides, to both anti-idiotypic CD8 + and CD4 + T cells, confirming that Ig-derived CDR epitopes are immunogenic [60, 61] .

Interaction amongst these three members of the Ig superfamily goes beyond their roles in lymphocyte activation or aiding the adaptive arm of the immune system (Fig. 1) . One possible implication is contraction of the immune response, the final phase after efforts 13 of the immune system to eliminate a pathogen and achieve homeostasis. After initial encounter with an immunogen, T cells and B cells undergo clonal proliferation, this implies a simultaneous expansion in CDR neoantigens that may elicit an effective antiidiotypic response. This natural anti-idiotype cellular and humoral immune response might function as a contraction element of the immune system, eliminating effector lymphocyte clones. The specific elimination hypothesis for contraction of the immune response could explain experimental evidence for epitope-specific CTL elimination, after prolonged exposure to a lymphocytic choriomeningitis virus (LCMV)-derived NP396 CTL epitope but not to exposure to other LCMV CTL epitopes [62] . If elimination occurs in differentiated effector or memory cells, it would be subject to further research. Other T cell dysfunctional processes may be involved such as exhaustion of epitope specific CTLs, which has been also demonstrated in the same model [63] .

Either clonal deletion, exhaustion or other T cell dysfunction processes may be occurring in cancer, which may reduce the repertoire of effector lymphocytes.

Experimental evidence came from studies in 2016 where tumor-infiltrating lymphocytes were only able to recognize 2 of 126 tumor-derived neoantigens from a stage IV melanoma patient [64] . The authors demonstrated that an outsourced naïve pool of T cells from healthy donors, indeed, has idiotypes that respond to those neoantigens, in contrast to the patient-derived own T cells [64] .

Other experimental clues concerning the idiotype-anti-idiotype network came from two separate experiments, which demonstrated specific idiotypic response inhibition after anti-idiotype intervention against two hapten groups, azophenylarsonates and phosphorylcholine, respectively [65, 66] . The proposed mechanism involved a haptenspecific idiotype BCR-Ab2 blocking interaction for hapten-specific inhibition of B lymphocyte responses [65, 66] . A similar theoretical mechanism might occur in the event of Ab recognition and blockade of either the TCR or the peptide-MHC complex; this could explain the reduction of the functional T cell repertoire, described above.

Furthermore, experiments in which T cells interact with naïve or resting anti-idiotypic T cells demonstrated the induction of anergy or apoptosis in the idiotypic T cell [58] .

Analogous with such immune inhibition by anti-idiotypic responses, it has been shown in autoimmune diseases that it is not the presence of the autoantibody against selfproteins, but the lack of Ab2 which is the underlying characteristic amongst patients [67, 68] .

Hypotheses concerning the maintenance of immune memory without the presence of Ags have been proposed. UytdeHaag and colleagues first established that CD5 + B lymphocytes could be activated by increases in CDR epitopes, derived from the expansion of Ag-specific B memory cells [69] . Theses CD5 + B lymphocytes may undergo affinity maturation to increase affinity to the Ag-specific B cell idiotype, then, after Ag clearance the V region of the anti-idiotype CD5 + B lymphocyte may serve as an Ag mimic to maintain memory cells [69] . Another hypothesis suggests that memory responses could be maintained, not only in the absence of persisting Ag, but also without long living memory cells. The interaction of idiotypic and anti-idiotypic responses could be an indefinite interaction, with no need for long-living memory B cells [70] . The same group found that peptidomimetics of the antigen in V regions of Ab2 are recognized by antigen-specific T cells and that maintenance of memory by the idiotype-anti-idiotype network could be extended to T cells as well [71] . The previous hypotheses agree with the need to generate T cell responses to help to achieve and regulate memory responses; furthermore, they propose mechanisms for affinity maturation based on idiotype-anti-idiotype interactions. Experimental designs and more importantly, results to confirm these hypotheses will be difficult to obtain but we cannot discard this phenomenon as a possible mechanism for immune memory maintenance [72] .

We believe that along with the already well-known functions of Abs, TCRs and MHC molecules there are still several not fully appreciated nor completely understood but related immunological phenomena. Interactions established by these molecules could expand our understanding of the immune system by adding non-canonical immune functions to already well-known molecules. Of interest, is the possibility to explore the immunogenicity of Ig superfamily members, as a promising way to find novel molecular vaccine candidates. Furthermore, we believe that the "internal image" of an originally encountered Ag, represented by a collection of polyclonal Ab2 molecules, may potentially bear resemblance to an even larger pool of epitopes/mimotopes, present within pathogens or cancer cells; these may possibly reflect their entire antigenic landscape. If this is true, then it could aid in the development of much needed vaccines against antigenically variable pathogens and cancer.

The authors have no potential conflict of interest to declare. 

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