Two signal half‐century: From negative selection of self‐reactivity to positive selection of near‐self‐reactivity

Abstract

With the emergence of clonal selection ideas in the 1950s, the development of immune cell repertoires was seen to require the negative selection of self‐reacting cells, with surviving cells exhibiting a broad range of specificities. Thus, confronting a universe of not‐self‐antigens, a potential host organism spread its resources widely. In the 1960s, the two signal hypothesis showed how this might work. However, in the 1970s an affinity/avidity model further proposed that anticipating a pathogen strategy of exploiting “holes” in the repertoire created by negative selection, hosts should also positively select near‐self‐reacting cells. A microbe mutating an antigen from a form foreign to its host to a form resembling that host should prevail over host defences with respect to that antigen. By mutating a step towards host self, along the path from non‐self to self, it should come to dominate the microbe population. By progressive stepwise mutations, such microbes would become better adapted, to the detriment of their hosts. But they would lose this advantage if, as they mutated closer to host self, they encountered progressively stiffer host defences. Thus, as described in the affinity/avidity model, positive selection of lymphocytes for specificities that were very close to, but not quite, anti‐self (ie, “anti‐near‐self”) should be an important host adaptation. While positive selection affects both B and T cells, mechanisms are uncertain. Converging evidence from studies of lymphocyte activation, either polyclonally (with lectins as “antigen‐analogs”) or monoclonally (by specific antigen), supports the original generic affinity/avidity model for countering mutations towards host self.

On integrity in immunity during ontogeny or how thymic regulatory T cells work

“…Then, negative selection and deleting all anti–self‐reactivities might allow a niche for survival of pathogens and parasites and would compromise the defensive function of the adaptive immune system. Vrisekoop and Forsdyke suggested that anti‐foreign T cell repertoire might be developed by being initially positively selected on near‐self in order to prevent such avoidance . The dynamic model (with the Integrity hypothesis) presented here is consistent with such a notion.…”

“…This protective (asylum) function of the immune system is arguably more than just tolerance, the latter being perhaps just “careless” non‐reactivity. Asylum would have similar benefits for the host immune defence as the selection of the repertoire on near‐self, proposed recently by Germain group and Forsdyke …”

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

“…That summer, we both left for North America and, sooner or later, both settled in Canada. A half‐century later, we both submitted “two‐signal” retrospectives to the Scandinavian Journal of Immunology …”

“…Here my interests included the development of my two‐signal hypothesis, which was different from that of Bretscher and Cohn . In recent times, there have been my personal retrospective in 2012 and my “half‐century” scientific retrospective in 2019 . Having not seen Bretscher's retrospective, I did not cite it in the latter (but I knew it was pending since I had declined a request to review).…”

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

“…6 In subsequent decades, positive selection ideas and their implications for cancer immunotherapy gained general support. 7 It is now recognized that small clones of 'anti-near-self' immune cells exist in patients and can be subject to extracorporeal expansion under tissue culture conditions prior to their return to the same patient. Specific anti-near-self T cell clones should be expandable extracorporeally in quantities that, when reintroduced, would suffice to target autologous cancer cells-a process that has become known as adoptive T cell transfer (ACT).…”