On 2017 Dec 03, Donald Forsdyke commented:

REDESIGNATING SELF AS NOT-SELF MARKERS

A cell's altruistic service to the population of cells that comprise its host organism may be compromised by a foreign pathogen or by a mutated driver cancer gene (both deemed "non-self"). Such intracellular compromising agents can first be addressed by internal sensing and auto-destructive mechanisms. Should one of these fail, then external sensing and destructive mechanisms, involving reactions with specific predatory T cells, may come into play. A compromised cell has the option of displaying peptides as pMHC complexes to see if they are recognized by members of T cell populations that, following thymic surveillance and deletion of nascent strongly self-reacting T cells, are programed to eliminate cells displaying non-self markers.

While such markers may arise from foreign proteins or mutated self proteins, Mishto and Liepe note that the scope of markers ("the antigenic landscape") can be greatly increased by redesignating potential self markers (unspliced peptides in pMHC complexes) as non-self (1). This creation of foreign from self is achieved by splicing and trimming non-contiguous peptides to create novel peptides that would not have passed thymic filters and so would be seen as non-self. Two corollaries of this are that such peptide splicing must not occur in the thymus and that, to militate against autoimmunity, extra-thymic specific splicing of separate protein segments would not occur randomly in uncompromised cells.

Thus, some elements of an internal sensing mechanism within a compromised cell would be needed to foster an extension of the antigenic landscape. The growing evidence for such a mechanism in the antigen presentation pathway (intracellular self/non-self discrimination) is presented elsewhere (2). I agree that "the unexpectedly large frequency and amount of … spliced peptides may … have profound implications for the concept of self/nonself peptide presentation" (3).

1.Mishto M, Liepe J. (2017) Post-translational peptide splicing and T cell responses. Trends in Immunology 38:904-915 Mishto M, 2017

2.Forsdyke DR (2015) Lymphocyte repertoire selection and intracellular self/not-self discrimination: historical overview. Immunology and Cell Biology 93:297-304. Forsdyke DR, 2015

3.Liepe J et al. (2016) A large fraction of HLA class I ligands are proteasome-generated spliced peptides. Science 354:354-358.Liepe J, 2016

On 2017 Dec 03, Donald Forsdyke commented:

REDESIGNATING SELF AS NOT-SELF MARKERS

A cell's altruistic service to the population of cells that comprise its host organism may be compromised by a foreign pathogen or by a mutated driver cancer gene (both deemed "non-self"). Such intracellular compromising agents can first be addressed by internal sensing and auto-destructive mechanisms. Should one of these fail, then external sensing and destructive mechanisms, involving reactions with specific predatory T cells, may come into play. A compromised cell has the option of displaying peptides as pMHC complexes to see if they are recognized by members of T cell populations that, following thymic surveillance and deletion of nascent strongly self-reacting T cells, are programed to eliminate cells displaying non-self markers.

While such markers may arise from foreign proteins or mutated self proteins, Mishto and Liepe note that the scope of markers ("the antigenic landscape") can be greatly increased by redesignating potential self markers (unspliced peptides in pMHC complexes) as non-self (1). This creation of foreign from self is achieved by splicing and trimming non-contiguous peptides to create novel peptides that would not have passed thymic filters and so would be seen as non-self. Two corollaries of this are that such peptide splicing must not occur in the thymus and that, to militate against autoimmunity, extra-thymic specific splicing of separate protein segments would not occur randomly in uncompromised cells.

Thus, some elements of an internal sensing mechanism within a compromised cell would be needed to foster an extension of the antigenic landscape. The growing evidence for such a mechanism in the antigen presentation pathway (intracellular self/non-self discrimination) is presented elsewhere (2). I agree that "the unexpectedly large frequency and amount of … spliced peptides may … have profound implications for the concept of self/nonself peptide presentation" (3).

1.Mishto M, Liepe J. (2017) Post-translational peptide splicing and T cell responses. Trends in Immunology 38:904-915 Mishto M, 2017

2.Forsdyke DR (2015) Lymphocyte repertoire selection and intracellular self/not-self discrimination: historical overview. Immunology and Cell Biology 93:297-304. Forsdyke DR, 2015

3.Liepe J et al. (2016) A large fraction of HLA class I ligands are proteasome-generated spliced peptides. Science 354:354-358.Liepe J, 2016