Friday, May 23, 2014

Understanding self-nonself discrimination by adaptive immune system

modified from 

Usharauli, David (2010, October 30). Understanding self-nonself discrimination by adaptive immune system. 


In 1969, Niels Jerne, later a Nobel laureate, predicted that "immunology will be completely solved within fifty years from now”, i.e. by 2019 (Jerne, 1969). Even earlier, in 1964, Frank Burnet, a Nobel laureate, complained that “the infant science [immunology] would soon run out of problems to solve” (Anderson, 1994). What was the basis for such a confidence? Maybe they knew better? After all, both were science demigods, acclaimed and worshipped and the modern immunology was of their creation. So what was this all about? 

The answer is the principle of self-nonself discrimination by adaptive immune system.
The adaptive immune system consists of T cells and B cells (clones). Each clone expresses a unique membrane receptor that (as the product of random gene recombination) is specific for an antigen, either self or nonself. Since an immune response can be initiated from a single clone (Stemberger et al, 2007), it is mandatory for the adaptive immune system to keep self-specific clones in check (tolerance) while at the same time allowing nonself-specific clones to respond (immunity). So how is this achieved? 

The value of any conceptual model rests on its predictive power. Initially, based on Peter Medawar’s (Nobel Lecture) experiments and Niels Jerne’s theoretical concept, the favored model was the one proposed by Frank Burnet. Burnet’s model of self-nonself discrimination required that all clones being generated during the embryonic stage when presumably only self-antigens were present (Burnet, 1957). At this stage, any clone that expressed a self-specific receptor would be deleted. Only nonself-specific clones would accumulate and subsequently respond to nonself-antigens when introduced by pathogen-invader. 

Soon, however, this model required major modification when it was shown experimentally that new clones of T and B cells are continuously generated long after birth. The problem was that according to the Burnet model, immediately after birth, each clone becomes spontaneously fully capable of responding to its cognate antigen, and given that newly generated clones can be self-specific, this scenario would have probably led to an unacceptably high frequency of self-specific responses, i.e. autoimmunity. A solution to this problem was introduced by Joshua Lederberg. According to the Lederberg model, each new clone (irrespective of whether it was generated during the embryonic stage or after birth) transits through a deletion-only stage and then it becomes spontaneously fully capable of responding to its cognate antigen (Lederberg, 1959). This deletion-only stage ensured that new clones with self-specificity would encounter their cognate self-antigens at this stage and become deleted. 

The Lederberg model, however, also failed for two reasons: first, deletion-only stage for newly generated clones was difficult to document experimentally, and second and more importantly, the Lederberg model did not account for the scenario when new self-antigens are introduced in the body, for example during puberty, pregnancy, lactation, etc. According to the Lederberg model these new self-antigens would have been considered as nonself (foreign) by the adaptive immune system and attacked, leading to unacceptably high frequency of autoimmune responses. In other words, the Lederberg model only works if self-antigens are constant (static) and it fails if self-antigens are changing (dynamic). 

All classical self-nonself discrimination models fail if self-antigens are changing. More recently, Melvin Cohn tried to save the classical self-nonself discrimination model by suggesting that the primary function for AIRE gene is to drive expression of “future” self-antigens during embryonic stage to create static view of self-antigen dynamics (Cohn, 2009).
The challenge posed by self-antigen dynamics was the major conceptual driving force behind the development of dendritic cell based innate “self-nonself” discrimination models of the past 20 years. Two models in particular completely revolutionized the modern immunology. The first one was introduced by late Charles Janeway and the second one by legendary Polly Matzinger (Janeway, 1992; Matzinger, 1994). 

In these models, “self-nonself” discrimination actually refers to immunity/tolerance fate of individual clones. Many weaknesses of Janeway’s model as it was originally understood (for example, how viruses stimulate innate immunity, how nonbacterial adjuvants, such as alum, work) is nowadays mainly resolved. While both these models can explain the immunological tolerance to changing “self”, both dendritic cell based “self-nonself” discrimination models so far failed (one in theory and another in practice) to explain the persistence of adaptive immune response to nonself (foreign) transplanted tissues. 

This maybe the result of downplaying the role that effector/memory T cells can play in perpetuating the immune response. Especially important is the relationship between effector/memory T cells and dendritic cells. If an effector/memory T cell with the self-specificity were able to deliver maturation signals to resting dendritic cells (and be equivalent in this regard to signals introduced by pathogen-invader or generated during tissue damage), then both Janeway’s and Matzinger’s models would fail because this scenario would lead to unacceptably high frequency of autoimmune responses. Interestingly, one paper published in Nature Medicine found that memory CD4 T cells were capable of inducing signals similar in nature to that induced by pathogen-invader (Strutt et al, 2010). If confirmed, this observation will necessitate yet another major modification of self-nonself discrimination model. In addition, to best of my knowledge, no one yet able to propose a working hypothesis how to incorporate Foxp3+ T regs in a predicable model of immune system function. After all, there are still 5 years left until 2019.

David Usharauli

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