Mantle-cell lymphoma neoantigens are derived from immunoglobulins

This week Nature published new study that could explain why B cell-derived lymphomas are not easily rejected by body's immune system. It also highlights some of the obvious forgetfulness regarding basic immunology concepts.  

In this paper, research group from Stanford analyzed neo-antigenic burden in untreated mantle-cell lymphoma, a subtype of B-cell non-Hodgkin lymphoma. Rather than simply doing whole exome-sequencing of lymphoma DNA to identify tumor associated non-synonymous somatic mutations, the authors focused on direct proteomic analysis of cancer MHC ligands, epitopes, by liquid chromatography and tandem mass spectrometry (LC–MS/MS). 

Interestingly, though the authors found 13–175 non-synonymous somatic mutations per patient within genes known to mutate in mantle-cell lymphoma, such as TP53, CCND1, none of the mutated neo-epitopes from these genes were actually presented by MHC molecules. Only exception were neo-antigens derived from immunoglobulin (Ig) genes themselves. Surprise, surprise! 

As the authors wrote "presentation of variable-region peptides by MHC-II suggests that Ig neoantigen recognition by CD4 does not inhibit lymphoma development." Why that could be the case? As we know, when B cell responds to antigen it undergoes hypermutations within its Ig variable regions. In essence, every responding B cell generates neo-antigens within its Ig molecules. These are antibodies the body is using to defend against pathogens. Obviously Ig hypermutated B cells (and memory B cells or plasma cells derived from such B cells) are not ordinarily rejected by body's own immune system. It is strange that the authors did not mention this obvious contradiction.  

David Usharauli

Checkpoint inhibitors, anti-PD1/anti-PD-L1 activities are channeled via CD28 co-stimulation

Two new back-to-back studies in Science showed that T cell recovery activity attributed to checkpoint inhibitors, anti-PD1/anti-PD-L1, is mediated via CD28 co-stimulation. One of the study focused on analysis of biochemical events leading to PD1 signaling in an in vitro reconstitution model and another study provided corroborating data using mouse model. 

Summary results from both studies suggest that anti-PD1/PD-L1 activity is lost when T cells lack co-stimulatory molecule CD28. However, readouts here are more complicated since PD-L1 itself could bind to CD28 ligand B7 molecule. Also, I noticed that by default T cells with inducible CD28 deficiency (CD28^f/f Cre^ERT2+) show less accumulation and/or survival (low cell density) compared to WT counterparts.

Another confusion has to do with the fact that at least in one of the clinical trials anti-CD28 antibodies produced severe cytokine release syndrome and program was discontinued. It could be that anti-PD1/PDL1 therapy activates only certain type of T cells while anti-CD28 could have targeted much larger T cell population.

David Usharauli

  

Minimal threshold for Treg repertoire diversity that prevents autoimmunity

If you have read enough of my blog you most likely noticed the preference for research articles that provide some new insight into Tregs' biology.

Few weeks back I analyzed new paper from Rudensky's lab that showed that 50% of mouse with Tregs expressing single TCR specificity were protected from lethal autoimmunity, though not from non-lethal or less lethal forms of  tissue autoimmunity. 

So what is the minimal Tregs TCRβ repertoire diversity required to suppress autoreactive T cells that escape thymic selection?

New paper from Thomas Malek's lab tried to found it out by serially transferring WT Tregs into Treg-deficient IL-2RβKO mice (1st and 2nd level recipients) and analyzing TCR repertoire pre and post transfer. They observed that after each transfer into IL-2RβKO Tregs TCR repertoire diversity got narrower and when it fell < 7000 unique Treg clonal specificity mice showed autoimmunity.

This threshold also correlated with pathological increase in CD62L^lowCD44^hi population that represents activated T cells typical to autoimmunity.

In summary, this study indicates that there is a minimal threshold for Tregs repertoire diversity that is essential to prevent non-lethal forms of autoimmunity.

David Usharauli