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Letter to the Editor

Apoptotic Loss of Thymic Lymphocytes in Acute Murine Zinc Deficiency

Department of Human Biology and Nutritional Sciences University of Guelph Guelph, ON, Canada N1G 2W1

Dear Editor:

King et al. (1 ) recently showed that apoptosis, primarily among CD4⁺CD8⁺ pre-T cells, accounts for the thymic atrophy observed in acute marginal zinc deficiency in mice. This is the latest in a series of investigations by the Michigan State group pertaining to the effect of acute zinc deficiency on lymphopoiesis in the primary lymphoid organs. I hope that my remarks will enhance the appreciation of these important studies. I would like to stimulate reconsideration of two points in relation to the models of acute nutritional deficiency that are in common use, viz., that thymic atrophy is a major factor in the associated peripheral lymphoid involution and that, in turn, peripheral lymphoid involution is decisive in the accompanying immune depression. King et al. (1 ) extrapolate their results to other acute nutritional deficiencies, notably of protein and energy, and my comments will reflect agreement with this point of view.

It is proposed that apoptosis within the thymus is a major factor in the reduction of peripheral T cell numbers in acute forms of malnutrition (1 ). However, I have difficulty aligning this proposition with classic studies of thymectomized rodents and rabbits. Neonatal thymectomy rapidly produces profound involution of peripheral lymphocyte populations in the blood and secondary lymphoid compartments (2 ,3 ). In contrast, however, involution of secondary lymphoid organs is modest and evident only on a chronic time course as a result of thymectomy at, or following, the age of weaning (4 ), although the blood lymphocyte count decreases acutely (4 ,5 ). These classic findings are consistent with current knowledge that the thymus continues to replenish the peripheral T-cell system into advanced age, but at a declining rate after the neonatal stage of life (6 ). I contend that acute malnutrition is rarely studied sufficiently early in life to permit reduced replenishment from the thymus to play a major role in the associated peripheral lymphoid involution. Rather, in almost all models of acute postnatal nutritional deficiency, the characteristic T-lymphopenia likely reflects glucocorticoid-mediated redistribution of T cells from the blood (7 ). Moreover, I suspect that the reduction in T-cell numbers in peripheral compartments other than the blood reflects mainly an apoptotic phenomenon within the periphery as illustrated recently for the macrophage in acutely protein-deficient adult mice (8 ). It seems to me that the Michigan State group has shown apoptosis to be a dominant mechanism of cellular loss from primary lymphoid organs in acute nutritional deficiencies, and that others are extending this very fundamental discovery to the periphery which, in the short term, involutes independently of events within the bone marrow or thymus.

King et al. (1 ) comment that reduction in numbers of lymphocytes (presumably with reference to the periphery wherein immune responses arise) "leads to" the depressed adaptive immune competence associated with acute malnutrition. I agree that lymphoid involution must contribute to malnutrition-associated immune depression, but I suspect that this is a less determinative component of the mechanism than is widely believed. My basis for this opinion is found in studies of protein- and/or energy-deficient weanling mice in which supplements of triiodothyronine prevented (9 –11 ), or even reversed (12 ) depression in adaptive immune competence. This immunomodulation was achieved despite unabated lymphoid atrophy in which cellular losses exceeded 90%. In fact, in combined protein and energy deficit (10 ,11 ), the hormonal intervention exacerbated peripheral lymphoid atrophy while promoting immune competence. Consequently, I consider lymphoid atrophy to be an important, but not decisive, factor in the immune depression associated with acute nutritional deficit.

In summary, I question whether thymic atrophy is a major factor in acute, malnutrition-associated involution of the peripheral T-cell system, and whether peripheral lymphoid losses are decisive to the immune depression of acute nutritional pathologies. Rather, I expect that the findings reported by King et al. (1 ) will lead us in more biologically profound directions. Apoptotic losses of pre-T cells presumably occur stochastically and, hence, may diminish the T cell repertoire in an unpredictable manner. King et al. (1 ) provide a compelling stimulus for much-needed studies of the T-cell repertoire in acute nutritional deficiencies. Such studies should add depth to our understanding of disease susceptibilities among the malnourished and should lead to increasingly rational and sophisticated therapeutic capabilities.

Manuscript received 3 July 2002. Revision accepted 9 December 2002.

LITERATURE CITED

1. King, L. E., Osati-Ashtiani, F. & Fraker, P. J. (2002) Apoptosis plays a distinct role in the loss of precursor lymphocytes during zinc deficiency in mice. J. Nutr. 132:974-979.[Abstract/Free Full Text]

2. Miller, J.F.A.P. (1961) Immunological function of the thymus. Lancet ii:748-749.

3. Archer, O. K, Papermaster, B. W. & Good, R. A. (1964) Thymectomy in rabbit and mouse: consideration of time of lymphoid peripheralization. Good, R. A. Gabrielsen, A. E. eds. The Thymus in Immunobiology 1964:414-435 Harper & Row New York, NY. .

4. Metcalf, D. (1960) The effect of thymectomy on the lymphoid tissues of the mouse. Br. J. Haematol. 6:324-333.

5. Miller, J.F.A.P. (1963) Role of the thymus in recovery of the immune mechanism in the irradiated adult mouse. Proc. Soc. Exp. Biol. Med. 112:785-792.

6. Kendall, M. D. (1991) Functional anatomy of the thymic microenvironment. J. Anat. 177:1-29.[Medline]

7. Sackstein, R. & Borenstein, M. (1995) The effects of corticosteroids on lymphocyte recirculation in humans: analysis of the mechanism of impaired lymphocyte migration to lymph node following methylprednisolone administration. J. Investig. Med. 43:68-77.[Medline]

8. Rivadeneira, D. E., Grobmyer, S. R., Naama, H. A., Mackrell, P. J., Mestre, J. R., Stapleton, P. P. & Daly, J. M. (2001) Malnutrition-induced macrophage apoptosis. Surgery 129:617-625.[Medline]

9. Filteau, S. M., Perry, K. J. & Woodward, B. (1987) Triiodothyronine improves the primary antibody response to sheep red blood cells in severely undernourished weanling mice. Proc. Soc. Exp. Biol. Med. 185:427-433.[Medline]

10. Perry, K. J., Filteau, S. M. & Woodward, B. (1988) Dissociation of immune capacity from nutritional status by triiodothyronine supplements in severe protein deficiency. FASEB J. 2:2609-2612.[Abstract]

11. Woods, J. W. & Woodward, B. D. (1991) Enhancement of primary systemic acquired immunity by exogenous triiodothyronine in wasted, protein-energy malnourished weanling mice. J. Nutr. 121:1425-1432.

12. Woods, J. W. & Woodward, B. (1994) Immunorestorative effect of triiodothyronine supplementation on the primary antibody response to sheep red blood cells following development of immune depression in protein-energy malnourished weanling mice. J. Nutr. Immunol. 3:3-12.

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