Saturday, May 6, 2017

antigen-specific Foxp3+ Tregs maintain tolerance in HLA-linked autoimmunity

This week Nature published new paper that has features of textbook studies. In it the authors showed that in human HLA transgenic mice model of Goodpasture disease [HLA+antigen]-specific Foxp3+ Tregs protected against autoimmune disease development.

Goodpasture disease is an "HLA-linked autoimmune renal disorder characterized by an immunodominant CD4+ T-cells [reactive to] self-epitope derived from the α3 chain of type IV collagen (α3135–145)". In humans presence of HLA-DR15 allele increases disease risk, while presence of HLA-DR1 allele is shown to be dominantly protective in trans with HLA-DR15.

Interestingly enough the authors reported similar pattern of HLA dependency in mouse model of human Goodpasture disease. Here, DR15+ mice were susceptible to disease development. DR1+ mice were resistant to disease development and DR15+DR1+ double-positive mice were healthy except when Tregs were depleted (all mice were on Fcgr2b−/− background, +/- Treg depletion, + immunization with peptide α 3135–145). 

It is not clear how Treg specific for DR1+peptide protects against autoreactive T cells specific for DR15+peptide. It is possible that there is some similarities between these HLA+peptides (cross-reactivity).

David Usharauli

Monday, April 17, 2017

HPV+ cancers express non-viral neo-antigens targeted during adoptive immunotherapy

Human papillomavirus can induce epithelial cancers. HPV oncoproteins (E6, E7) are thought to be clinically-relevant antigenic targets for antigen-specific immunotherapy. 

New study in Science showed however that in patients "with HPV+ metastatic cervical carcinoma who experienced complete cancer regression" after adoptive immunotherapy, T cells target cancer-specific mutated neo-antigens, not just viral antigens.

These results indicate that HPV+ cancer patients could benefit from adoptive transfer of T cells specific for non-viral oncoproteins  (though it is not clear from this study whether non-viral tumor neo-antigen specific T cells or HPV oncoprotein specific T cells were responsible tumor regression).

David Usharauli

Sunday, April 9, 2017

The role of LAG3 in Tregs and how infection modulates immune response to dietary antigens

Lymphocyte activation gene 3 (LAG3) is the most recent checkpoint inhibitor to be targeted in the clinic. LAG3 has been shown to dampen T cell activity. For instance, diabetic-prone mice deficient in LAG3 exhibit accelerated autoimmune diabetes with 100% of KO mice developing it. As Foxp3+ regulatory T cells express LAG3 it was thought that it played a role in Treg activity.

Surprisingly, however, according to new study mice with Treg-specific LAG3 deficiency showed improved rather than diminished protection against development of autoimmune diabetes. 

This unexpected outcome requires rethinking the role LAG3 within immune system. Systemic inhibition of LAG3 by blocking antibodies could enhance tumor progression, for example, by stimulating tumor-infiltrating Tregs.

Another paper, however, with ambitious title I read this week fell flat upon examining actual data. Its objective was to examine how viral infection could modify host's immune response to dietary antigens and lead to celiac disease. According to paper "celiac disease (CeD) is a complex immune disorder with an autoimmune component in which genetically susceptible individuals expressing the human leukocyte antigen (HLA) DQ2 or DQ8 molecules display an inflammatory T helper 1 (TH1) immune response against dietary gluten present in wheat".

To replicate hypothetical scenario that could lead to celiac disease, the authors infected mice with reovirus and simultaneously gave them nominal antigen, OVA, as a dietary antigen. As virus induced inflammation, it led to reduced numbers of Foxp3+ Tregs and parallel increase in Th1 transcription factor, T-bet+ T cells specific for dietary antigen.

The authors concluded that viral infection could modify body's response to dietary antigens. However, such conclusion is premature here as it is not obvious that those T cells that were destined to become Foxp3+ regulatory T cells were actually diverted into Th1 lineage. It is not clear either what would be the outcome of dietary antigen exposure once viral infection is cleared or how long the effect of viral infection modifies a physiological response to dietary antigens.

David Usharauli