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I have previously discussed how the thymus, the organ responsible for T
cell generation and central tolerance, is particularly sensitive to
malnutrition, and, thus, could be adversely affected by celiac disease,
especially during the critical naive T cell repertoire building stage of
early childhood.  The thymus shrinks after puberty, but, only recently
(1999), was it determined that the thymus continues to generate naive T
cells in adults.  The following study sheds light on the status of T cell
repertoire as we age.

For immune protection, it is desireable to have a naive T cell repertoire
which expesses a wide range of differing T cell receptors (TCR) able to
attack a wide range of pathogens and able to properly regulate immune
response and tolerance.  The study shows that the numbers of naive T cells
remain fairly constant as we age, but T cell receptor variation declines,
reducing the effectiveness of the immune system.  Naive T cells can replace
themselves by dividing and proliferating outside of the thymus (in the
periphery.)  But where the thymus can generate naive T cells with new and
differing T cell receptors, naive T cells generated in the periphery simple
duplicate existing T cell receptors leading to a restricted TCR repertoire.

With regard to celiac disease and autoimmune disorders it is particularly
interesting to note:  "Additionally these cells, which constitute the
majority of naive CD4(+) T cells in the elderly, display signatures of
recent TCR engagement."  In active celiac disease, CD4(+) T cells with a
TCR affinity for gluten peptides would be proliferating and engaging in an
attack on gluten.  Therefore, as celiacs age, the TCR repertoire would tend
to have a large proportion of TCR with affinity for gluten.  The restricted
TCR repertoire would leave us more vulnerable to infections and autoimmune
disorders.

So celiacs could be getting a double-whammy at both ends of our lives:
impaired thymus function and reduced T cell repertoire during childhood
from malabsorption; and highly restricted TCR repertoire as we age
resulting from immune activity against gluten.

Strategies and treatments which revitalize thymus function to increase the
generation of new naive T cells could improve the health of celiacs.

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Eur J Immunol. 2005 May 23; [Epub ahead of print]

Post-thymic in vivo proliferation of naive CD4(+) T cells constrains the
TCR repertoire in healthy human adults.

Kohler S, Wagner U, Pierer M, Kimmig S, Oppmann B, Mowes B, Julke K,
Romagnani C, Thiel A.

German Rheumatism Research Centre, Clinical Immunology, Berlin, Germany.

In spite of thymic involution early in life, the numbers of naive CD4(+) T
cells only slowly decline in ageing humans implying peripheral post-thymic
naive CD4(+) T cell expansion. This proliferation may compensate for
continuous activation and death of naive CD4(+) T cells but may also have
negative consequences for protective immunity. Here we show that naive CD4
(+) T cells that have proliferated in the periphery are characterized by a
highly restricted oligoclonal TCR repertoire. Additionally these cells,
which constitute the majority of naive CD4(+) T cells in the elderly,
display signatures of recent TCR engagement. Our results demonstrate for
the first time that peripheral post-thymic proliferation of naive CD4(+) T
cells in healthy human individuals causes a significant contraction of the
peripheral TCR repertoire. This age-dependent deterioration of CD4(+) T
cell immunity could entail ageing-associated autoimmunity, increased
susceptibility to infection or cancer and decreased efficiency of
vaccination.

PMID: 15909312 [PubMed - as supplied by publisher]

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