Beyond T-Cells: Functional Characterization of CTLA-4 Expression in Immune and Non-Immune Cell Types

Abstract

The immune response consists of a finely-tuned program, the activation of which must be coupled with inhibitory mechanisms whenever initiated. This ensures tight control of beneficial anti-pathogen and anti-tumor responses while preserving tissue integrity, promoting tissue repair, and safeguarding against autoimmunity. A cogent example of this binary response is in the mobilization of co-stimulatory and co-inhibitory signaling in regulating the strength and type of a T-cell response. Of particular importance is the costimulatory molecule CD28 which is countered by CTLA-4. While the role of CD28 in the immune response has been thoroughly elucidated, many aspects of CTLA-4 biology remain controversial. The expression of CD28 is largely constrained to constitutive expression in T-cells and as such, teasing out its function has been somewhat simplified by a limited and specific expression profile. The expression of CTLA-4, on the other hand, while reported predominantly in T-cells, has also been described on a diverse repertoire of cells within both lymphoid and myeloid lineages as well as on the surface of tumors. Nonetheless, the function of CTLA-4 has been mostly described within the context of T-cell biology. The focus on T-cell biology may be a direct result of the high degree of amino acid sequence homology and the co-expression pattern of CD28 and CTLA-4, which initially led to the discovery of CTLA-4 as a counter receptor to CD28 (for which a T-cell-activating role had already been described). Furthermore, observations of the outsized role of CTLA-4 in Treg-mediated immune suppression and the striking phenotype of T-cell hyperproliferation and resultant disease in CTLA-4−/− mice contribute to an appropriate T-cell-centric focus in the study of CTLA-4. Complete elucidation of CTLA-4 biology, however, may require a more nuanced understanding of its role in a context other than that of T-cells. This makes particular sense in light of the remarkable, yet limited utility of anti-CTLA-4 antibodies in the treatment of cancers and of CTLA-4-Ig in autoimmune disorders like rheumatoid arthritis. By fully deducing the biology of CTLA-4-regulated immune homeostasis, bottlenecks that hinder the widespread applicability of CTLA-4-based immunotherapies can be resolved.

Targeting Impaired Antimicrobial Immunity in the Brain for the Treatment of Alzheimer’s Disease

“…Sometimes drugs approved for other diseases (eg cancer) may be repurposed for other chronic inflammatory diseases such as AD. This could be the case for the tyrosine kinase inhibitors (eg dasatinib), immune checkpoint inhibitors (eg PD1, PD1L, CTLA-4) in non-T cells such as dendritic cells 351 which can increase the innate immune response and prime the adaptive immune response. In animal studies, checkpoint inhibitors enhanced the cognitive performance 352–354 but this treatment appears nonconclusive in human studies.…”

Identification of CTLA-4-Positive Cells in the Human Tonsil

“…What these works have in common is that they were performed on isolated cells using FACS, WB, RT-PCR, and flow cytometry, while none were performed with the use of immunohistochemical staining on tissue sections. Immunohistochemical approaches were applied only in single studies reviewed by Oyewole-Said et al [18], and in some of these reports anti-CTLA-4 antibodies of clones BNI3 and 14D3 were used. However, the antibody manufacturer Abcam removed its recommendation to use the anti-CTLA-4 antibody (clone BNI3, #ab19792) in immunohistochemical approaches following customer feedback (https://www.abcam.com/ctla4-antibody-bni3-ab19792.html, accessed on 15 April 2021).…”

“…However, the antibody manufacturer Abcam removed its recommendation to use the anti-CTLA-4 antibody (clone BNI3, #ab19792) in immunohistochemical approaches following customer feedback (https://www.abcam.com/ctla4-antibody-bni3-ab19792.html, accessed on 15 April 2021). Likewise, another clone of the anti-CTLA-4 antibody (clone 14D3) that was used in studies reviewed by Oyewole-Said et al [18] is recommended for FC/FACS, but not for immunohistochemical applications (https://www.citeab.com/antibodies/2039829-16-1529-cd152 -ctla-4-monoclonal-antibody-14d3-f, accessed on 15 April 2021). In contrast to the studies mentioned above, the aim of our study was to analyze the distribution pattern of CTLA-4 in cells other than T-lymphocytes in tissue sections in situ.…”

“…Of special interest is the paper by Pistillo et al [ 17 ], who first described the reactivity and function of CTLA-4 in different cell types. These and other publications are discussed in the review by Oyewole-Said et al, [ 18 ]. What these works have in common is that they were performed on isolated cells using FACS, WB, RT-PCR, and flow cytometry, while none were performed with the use of immunohistochemical staining on tissue sections.…”

Immune Checkpoints in Pediatric Solid Tumors: Targetable Pathways for Advanced Therapeutic Purposes

“…CTLA-4, also named CD152, is an inhibitory receptor belonging to the immunoglobulin (Ig) super-family, which negatively regulates T cell responses, thus avoiding the generation of potential auto-reactive T cells in the early activation phase [ 130 ]. CTLA-4 is structurally homologous to the co-stimulatory molecule CD28 and competes with the latter molecule for the same ligands.…”