What is the ‘immune self,’ and how can this concept benefit immunological research?

By Hugo Francisco de Souza

In a recent perspective review, researchers attempt to collate and discuss scientific knowledge on the concept of the ‘immune self’ and use raw T cell assays, nine amino-long pathogen-derived peptides, and human proteomes to attempt to define this often cited yet hitherto vague concept. Given the central role of similarity-to-self in an increasing number of immunological fields, this review highlights scientific advances in understanding the mechanisms underpinning adaptive immune responses and the challenges hindering the assessments and definitions of self-similarity.

Study: A journey to your self: The vague definition of immune self and its practical implications. Image Credit: Corona Borealis Studio / Shutterstock

Study: A journey to your self: The vague definition of immune self and its practical implications. Image Credit: Corona Borealis Studio / Shutterstock

The review summarises the evolution of the immune self since its introduction in 1949, the role of adaptive immune recognition and its mode of operation, and the function of the T cell repertoire and its development. It further touches upon the spatiotemporal variability of the immune self and how this variability leads to significantly inconsistent outcomes in some immunological studies. Finally, the review suggests means for standardizing and enhancing similarity measures, which, if successful, could dramatically improve immunological research moving forward.

What is the concept of the immune self, and how has it evolved over the decades?

Adaptive immunity is the ability of specific lymphocytes to differentiate between self and non-self (foreign) antigens and defend the body by selectively destroying non-self-peptides. This concept is possibly the most crucial factor in several immunological medical domains and is increasingly being explored across cancer immunotherapy, vaccine design, pathogen identification, and autoimmune disorders (including allergies). A growing body of literature elucidates the importance of peptides, short amino acid chains linked via peptide bonds, in providing the adaptive immune system with the information required to effectively distinguish between self and non-self particles.

This has resulted in the proposal of the ‘immune self’ concept, which postulates that self-similarity is a fundamental determinant of immune recognition. First introduced by Frank MacFarlane Burnet in 1949, the immune self-concept and its sister, the self-nonself theory, have substantially evolved over the decades. Initially driven by observations from Medawar’s early transplantation experiments, Nils K. Jerne (1974; eigen-behavior theory), Polly Matzinger (1994; danger theory), and most recently, evidence from research conducted independently by Waldmann, Mitchison, and Janeway has refined the immune self-concept from ‘all body elements are self, and foreign elements are non-self’ to the most recent ‘infectious non-self (foreign and usually harmful) versus noninfectious self (safe) elements.’

Practical examples of the concept’s use and challenges in its definition

The degree of similarity to self-peptides has been observed to impact the strength of adaptive immune response. This observation is now actively utilized to improve research outcomes across various immunological fields, such as cancer immunotherapy, vaccine development, and autoimmune disorders. 1. Cancer immunotherapy – Mutated cancer peptides have sequences different from normal somatic cells. The degree of self-similarity has been shown to determine whether these cancerous cells are identified as harmful (low self-similarity) or remain masked from the immune system (high self-similarity). The current goal of neoantigen vaccines (cancer immunotherapy) is to identify mutant peptides with low self-similarity and selectively present these to the immune system, thereby triggering the latter to help destroy the cancer.

2. Vaccine development – in a similar fashion, “pathogen-associated peptides resembling our self-proteins are less likely to be targeted by the immune system.” Designing vaccine elements that help the adaptive immune system identify normally invisible (high self-similarity) pathogenic peptides as foreign allows researchers and clinicians to recruit humans’ natural defenses in the war against disease instead of relying solely on therapeutic interventions, the latter of which may trigger autoimmune reactions. 3. Pathogen-triggered autoimmune disorders – In some cases, pathogens with high self-similarity to human peptides can sometimes be identified as both harmful and self. This, in turn, primes the adaptive immune system to target the pathogen for destruction while also targeting similar safe somatic peptides, resulting in expressive autoimmune side effects.

Unfortunately, despite years of research and countless citations referencing the immune self-concept, a standard definition of the concept remains elusive. Pradeau has identified at least five definitions of self in recent immunological literature. Ironically, despite decades of revision, Burnet’s original “genetic” self-concept remains the most used.

So, how can this definition challenge be overcome?

To precisely define self and non-self peptides and, in turn, self-similarity, we must first improve our understanding of the adaptive immune cascade and its constituent components. In brief, the fundamental unit of adaptive immune recognition comprises the major histocompatibility complex (MHC) molecules (called the human leukocyte antigen [HLA] in humans), the peptide being presented (and, in turn, identified as self or non-self), and the T cell receptor.

“…the quality of the T cell response is collectively influenced by various factors, including the interaction between the peptide and the HLA, the sequence and 3D structure of the presented peptide, TCR affinity and avidity, the involvement of costimulatory and inhibitory receptors, the dosage of the antigen, and the cytokine milieu. Moreover, T cells make collective and not individual decisions, which is contingent on quorum sensing and mediated by cytokines received from other T cells in the surrounding environment. A comprehensive understanding of T cell repertoire development clarifies why the similarity to self-proteins plays a crucial role in shaping the nature of the immune response.”

The presented peptides trigger the formation of the T cell repertoire within the thymus. Lymphoid progenitor cells (‘thymocytes’) first undergo positive selection, a process mediated by HLA-presented self-peptides. The degree of thymocyte binding (governed by the degree of self-similarity) decides the number of thymocytes that eventually become Tregs – the mediators of immune tolerance. Thymocytes that fail to bind to the HLA-presented self-peptides are destroyed (~95% of all thymocytes).

Treg-mediated self-tolerance is increasingly attributed to the evolutionary constraints of self-recognition and, more recently, the spatiotemporal variability of the immune self. These factors are hypothesized to be the mechanisms underpinning substantial variability in patients’ responses to immune therapy – instances of the same individual responding adversely to immune therapy that formerly presented positive outcomes have been confounding in the past. Still, recent research has identified that the T cell repertoire can change based on age and environment.

Conclusions

While the present review fails to present a single unifying definition for the immune self-concept, it highlights the theories and evolution of the concept over time and the molecular mechanisms governing the adaptive immune system’s differentiation between self- and non-self peptides. This will allow future researchers to focus on the mechanistic underpinnings of immunological responses rather than being constrained by archaic theories, which have now largely been disproven yet continue to be actively cited in current literature.

“…the vague definition of immune self presents a considerable challenge in vaccine design and neoantigen identification, as similarity to immune self is a crucial factor to consider. The complexity of adaptive immune recognition and the vast range of potential peptide sequences make it difficult to accurately assess self-similarity using traditional methods. Nevertheless, ongoing technological advancements hold the potential to expedite the future development of precise and personalized measures.”

Journal reference:

• Koncz, B., Balogh, G. M., & Manczinger, M. (2024). A journey to your self: The vague definition of immune self and its practical implications. In Proceedings of the National Academy of Sciences (Vol. 121, Issue 23). Proceedings of the National Academy of Sciences, DOI – 10.1073/pnas.2309674121, https://www.pnas.org/doi/10.1073/pnas.2309674121