Tumor Immunology Meeting 29-05-2017

Learning by example:

How T cell cross-reactivity helps the immune system learn self-nonself discrimination

Inge Wortel
Department of Tumor Immunology,
Radboudumc

T cell diversity & negative selection: a problem of numbers

The immune system's T cell repertoire has to:

  • recognize >1015 foreign epitopes ... 1
  • ... while tolerating hundreds of thousands of potential self epitopes

Diversity

Tolerance

  • Healthy adults have many autoreactive T cells 2
  • T cells cannot see every self peptide in the thymus

1 Sewell (2012). Nature Reviews Immunology.2 Yu et al (2015). Immunity.   Images adapted from The Immune System, 3rd ed.(2009), Garland Science.

Generalization

The T cell repertoire needs to learn which epitopes are "self" based on only a few examples in the thymus

Generalization:
Infer common features of a group of objects from a few examples

Generalization: example

Group of objects : paintings by Rembrandt
A description would be tedious! $\rightarrow$ Give examples:

Generalization: example

Now find the third Rembrandt...

or

Can the immune system generalize?

Can the T cell repertoire infer whether an epitope is "self" or "foreign" because of generalization during negative selection?

Only if:

1. Self epitopes have some common features

2. T cells can see those similarities

Generalization through cross-reactivity?

Cross-reactivity: T cells recognize multiple (related) epitopes

A simple model of TCR-pMHC recognition

Three ingredients needed:

1 Epitope
2 (CD8+) TCR
3 Matching rule

A simple model of TCR-pMHC recognition

Three ingredients needed:

1 Epitope peptide that binds MHC-I (9-mer)
2 (CD8+) TCR
3 Matching rule

A simple model of TCR-pMHC recognition

Three ingredients needed:

1 Epitope peptide that binds MHC-I (9-mer)
2 (CD8+) TCR "implicit" motif & matching length $k$
3 Matching rule

A simple model of TCR-pMHC recognition

Three ingredients needed:

1 Epitope peptide that binds MHC-I (9-mer)
2 (CD8+) TCR "implicit" motif & matching length $k$
3 Matching rule at least $k$ matches in a row

$k$ tunes cross-reactivity

Which peptides can bind to a given TCR?

$k$ # binders frequency
6 1 1 in 64,000,000
5 39 1 in 650,000
4 1,160 1 in 55,000
3 30,800 1 in 2,000
2 766,879 1 in 80
1 16,954,119 1 in 4
lower $k$ $\rightarrow$ less specific
$\rightarrow$ more cross-reactive

Simulating negative selection

Negative selection removes highly cross-reactive T cells

Fewer T cells survive if:

  • More self epitopes are "seen" in the thymus 1,2
  • T cells are more cross-reactive (low $k$)
1 Košmrlj et al. (2008) PNAS.
2 Huseby et al. (2005) Cell.

Simulating negative selection

Precursor frequency: specific cells per million T cells

Choice of "training" epitopes in thymus

Cross-reactivity & generalization: tolerance

Higher tolerance if: - More self "seen"
- "Smart" choice of training set
- Cross-reactivity (lower $k$)

Cross-reactivity & generalization: foreign recognition

Also foreign epitopes that "look like self" are deleted!
$\rightarrow$ overgeneralization

Overgeneralization

When T cells "see" all self epitopes during selection:

$\rightarrow$ With too high cross-reactivity ($k$ = 3), no cells survive that can detect foreign epitopes.

Summary: self-nonself discrimination (I)

Generalization in the immune system:

  • Cross-reactivity helps achieve tolerance
  • Cross-reactivity impairs the ability to recognize foreign epitopes
  • $\rightarrow$ self-nonself discrimination relies on balance

Measuring balance

If T cells do not see the whole "self": "unseen self" might still be recognized!
$\rightarrow$ but maybe with a lower precursor frequency?

Learning score: 0 = no difference between "unseen self" and "foreign"
1 = perfect discrimination

How could the thymus be "smart"?

Computed "smart" set is enriched in rare AAs, depleted of common AAs

$\rightarrow$ Could enrichment of rare AAs help self-nonself discrimination?

How could the thymus be "smart"?

Bias for peptides with rare AAs:
$\rightarrow$ enough to improve self-nonself discrimination?

Summary: self-nonself discrimination (II)

Generalization in the immune system:

  • Cross-reactivity helps achieve tolerance
  • Cross-reactivity impairs the ability to recognize foreign epitopes
  • $\rightarrow$ self-nonself discrimination relies on balance

Self-nonself discrimination cannot be perfect!

  • self and foreign are similar
  • risk of holes in the repertoire
  • smart presentation of self peptides helps

Outlook & concluding remarks

Test robustness:

  • "foreign": other pathogens than HIV
  • model: try a different "matching rule"

How important in vivo?

  • Validate through testable predictions:
    $\rightarrow$ rare amino acids enriched in the thymus?
    $\rightarrow$ e.g. by thymoproteasome/TAP/...

Acknowledgements

Tumor Immunology, Nijmegen

  • Johannes Textor
  • Jolanda de Vries
  • Carl Figdor
  • Human DLM


Funding

  • Radboudumc PhD grant

Theoretical Biology, Utrecht

  • Rob de Boer
  • Can Keşmir