On certain two‐signal perspectives of lymphocyte activation and inactivation, thymic G‐quadruplexes, and the role of aggregation in self/not‐self discrimination

Forsdyke, Donald R.

doi:10.1111/sji.12797

Cited by 2 publications

(4 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…negative selection that might result in tolerance). 21,22 Yet Burnet expressed optimism that somehow, despite the proposed inhibition (dormancy) or deletion of potentially self-reacting cells, an organism's immune system might be harnessed to control its own cancer cells. 15 In his view, for their immunological targeting the generation of cancer cells would seem to require extreme mutations (in degree or number) that would have altered normal 'self' cells to pathological 'non-self'.…”

Section: Discriminates Non-self From Selfmentioning

confidence: 99%

“…17 Theoretical arguments that the somatic development of immune cell repertoires would focus on 'near-self' (rather than 'altered self') 24 have appeared to have solved the immunologists' conundrum. 21,22,[25][26][27] Yet, for getting peptides to the surface of APCs 'an underappreciated orchestration … needs to take place'. 23…”

Section: Discriminates Non-self From Selfmentioning

confidence: 99%

“…positive selection that might result in immunity) and high concentrations would inhibit (i.e. negative selection that might result in tolerance) 21,22 …”

Section: Antigen Concentration Discriminates Non‐self From Selfmentioning

confidence: 99%

See 2 more Smart Citations

Aggregation‐prone peptides from within a non‐self‐protein homoaggregate are preferred for MHC association: Historical overview

Forsdyke

2023

Scand J Immunol

Self Cite

View full text Add to dashboard Cite

New technologies assist re‐evaluation of hypotheses on generation of immune cell repertoires and distinctions of self from non‐self. Findings include positive correlations between peptide propensities to aggregate and their binding to major histocompatibility complex (MHC) proteins. This recalls the hypothesis that foreign proteins may homoaggregate in host cytosols prior to releasing their peptides (p) to form pMHC complexes. Clues to this included aggregation‐related phenomena associated with infections (rouleaux formation, pyrexia, certain brain diseases). By virtue of ‘promiscuous’ gene expression by thymic presenting cells – perhaps adapted from earlier evolving gonadal mechanisms – developing T cells monitor surface pMHC clusterings. This evaluates intracellular concentrations of the corresponding proteins, and hence, following Burnet's two signal principle, degrees of self‐reactivity. After positive selection in the thymic cortex for reactivity with ‘near‐self’, high‐level pMHC clustering suffices in the medulla for negatively selection. Following Burnet's principle, in the periphery low‐level clustering suffices for T cell stimulation and high‐level clustering again provokes negative selection (immunological tolerance). For evolving intracellular pathogens, fine‐tuned polymorphisms of their host species have limited to ‘near‐self’ some mimicking adaptations. It is proposed that while entire pathogen proteins may have evolved to minimize their aggregability, the greater aggregability of their peptides remains partially hidden within. Two‐step proofreading mechanisms in prospective hosts select proteins containing aggregable peptide for the generation of pMHC clusters at the surface of presenting cells. Through mutations, some proteins of pathogens and cancer cells tend to converge towards the host ‘near‐self’ that its T cells have auditioned to address.

show abstract

Section: Discriminates Non-self From Selfmentioning

confidence: 99%

Section: Discriminates Non-self From Selfmentioning

confidence: 99%

See 1 more Smart Citation

Aggregation‐prone peptides from within a non‐self‐protein homoaggregate are preferred for MHC association: Historical overview

Forsdyke

2023

Scand J Immunol

Self Cite

View full text Add to dashboard Cite

show abstract

“…26,45,46 The effects of one of these (dGTP generated in deoxyguanosine-containing media) are now seen by immunologists as influencing an enzyme of major importance in creating antibody diversity. 47 While nucleosides and nucleotides may have influenced interpretations of results in earlier literature, fortunately they are not present in RPMI 1640, a currently popular medium. 48 In summary 21 :…”

Section: Transcription Factormentioning

confidence: 99%

Metabolic optimization of adoptive T cell transfer cancer immunotherapy: A historical overview

Forsdyke

2020

Scand J Immunol

Self Cite

View full text Add to dashboard Cite

After prolonged extracorporeal multiplication in physiological culture media, there can be curative infusions of a cancer patient's own cytotoxic T cells (adoptive T cell transfer; ACT), which must achieve efficient activation in potentially adverse tumour microenvironments. With spectacular, yet irregular, success, improvements are needed. Developing lymphoid cells are biologically selected, not only for ‘near‐self’ reactivity (positive selection), but also to avoid self‐reactivity (negative selection). Thus, success requires harnessing near‐self cells while avoiding extreme autoimmune phenomena. Abrupt metabolic changes accompanying T cell activation to leave the G0 stage and enter the G1 stage of the cell cycle (eg enhanced glycolysis) are accompanied by increased transcription of the G0S9 gene that mediates salvage synthesis of NAD+ from nicotinamide; the latter has recently been shown to increase the efficiency of ACT. Despite theoretical and experimental advances, there has not been parallel progress in simulating in vivo conditions with culture media that were initially formulated for their positive benefits for tumour cell lines (cell survival and proliferation). Yet for lymphoid cells, inhibition or death (ie immunological tolerance) is as important as their activation and proliferation (immunological response). Thus, use of media optimized for the latter may mask the former. The resilience of established culture protocols may have been partly politically driven. However, unphysiological conditions have sometimes yielded fortuitous insights. Optimization of culture media for specific tissues must consider the nature of problems addressed in research settings and the need to avoid mishaps in clinical settings.

show abstract

On certain two‐signal perspectives of lymphocyte activation and inactivation, thymic G‐quadruplexes, and the role of aggregation in self/not‐self discrimination

Cited by 2 publications

References 62 publications

Aggregation‐prone peptides from within a non‐self‐protein homoaggregate are preferred for MHC association: Historical overview

Aggregation‐prone peptides from within a non‐self‐protein homoaggregate are preferred for MHC association: Historical overview

Metabolic optimization of adoptive T cell transfer cancer immunotherapy: A historical overview

Contact Info

Product

Resources

About