- Email: [email protected]
Losing TREC with Age
Immunity
Previews REFERENCES Dong, J., Ivascu, C., Chang, H.D., Wu, P., Angeli, R., Maggi, L., Eckhardt, F., Tykocinski, L., Haefliger, C., Mo¨wes, B., et al. (2007). J. Immunol. 179, 2389–2396. Hill, J.A., Feuerer, M., Tash, K., Haxhinasto, S., Perez, J., Melamed, R., Mathis, D., and Benoist, C. (2007). Immunity 27, 786–800. Hoffmann, P., Boeld, T.J., Eder, R., Huehn, J., Floess, S., Wieczorek, G., Olek, S., Dietmaier, W., Andreesen, R., and Edinger, M. (2009). Eur. J. Immunol. 39, 1088–1097. Klein, L., and Jovanovic, K. (2011). Semin. Immunol. 23, 401–409. Lio, C.W., and Hsieh, C.S. (2008). Immunity 28, 100–111. Miyao, T., Floess, S., Setoguchi, R., Luche, H., Fehling, H.J., Waldmann, H., Huehn, J., and Hori, S. (2012). Immunity 36, this issue, 262–275.
Figure 1. Commitment and Differentiation of Foxp3+ Treg Cells Differentiation of Treg cells along distinct pathways might be associated with a differential degree of commitment. Thymic development appears to be characterized by early commitment, even before expression of Foxp3, and preferential adoption of a stable phenotype that is imprinted by CpG demethylation in the TSDR (CNS2). Differentiation of Foxp3+ cells in the periphery includes a larger proportion of ‘‘promiscuous Foxp3+’’ cells that upregulate Foxp3 without acquisition of a stable suppressive phenotype, giving rise to both ‘‘exFoxp3’’ cells convertible into effector cells as well as to stable, peripherally induced Treg cells.
well as counteracting environmental signals and cell-intrinsic developmental predispositions. Answering of these questions will not only be of central importance for the
understanding of the origin of the Treg cell lineage, but also better define the conditions to be met when induction or expansion of Foxp3+ Treg cells for therapeutic application is intended.
Polansky, J.K., Kretschmer, K., Freyer, J., Floess, S., Garbe, A., Baron, U., Olek, S., Hamann, A., von Boehmer, H., and Huehn, J. (2008). Eur. J. Immunol. 38, 1654–1663. Rubtsov, Y.P., Niec, R.E., Josefowicz, S., Li, L., Darce, J., Mathis, D., Benoist, C., and Rudensky, A.Y. (2010). Science 329, 1667–1671. Schallenberg, S., Tsai, P.Y., Riewaldt, J., and Kretschmer, K. (2010). J. Exp. Med. 207, 1393– 1407. Zhou, X., Bailey-Bucktrout, S.L., Jeker, L.T., Penaranda, C., Martı´nez-Llordella, M., Ashby, M., Nakayama, M., Rosenthal, W., and Bluestone, J.A. (2009). Nat. Immunol. 10, 1000–1007.
Losing TREC with Age Shirley L. Zhang1 and Avinash Bhandoola1,* 1Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA *Correspondence: [email protected] DOI 10.1016/j.immuni.2012.02.005
In this issue of Immunity, den Braber et al. (2012) highlight differences in naive T cell lifespan between mice and humans. Their data suggest that mechanisms of naive T cell maintenance may differ between mice and men. How long do naive T cells live and how are they replenished? A short life span for naive T cells would necessitate faster rates of replenishment, whereas increased life span would accommodate
slower rates of replenishment. Work in this issue of Immunity by den Braber et al. (2012) examines the longevity of naive T cells. Their data suggest that mechanisms maintaining T cells with
naive phenotypes might differ in humans and mice (den Braber et al., 2012). The life span of mice is 2 years, whereas humans live much longer. Do the naive T cells of mice and humans
Immunity 36, February 24, 2012 ª2012 Elsevier Inc. 163
Immunity
Previews
also have different life spans? Such a possibility had been Tough and Sprent measured previously suggested in other T cell turnover in mice by human studies of naive T cells using bromodeoxyuridine (Dutilh and de Boer, 2003; (BrdU) treatment to label Kilpatrick et al., 2008). One dividing cells. These results consequence of maintaining indicated that naive T cells T cell populations chiefly in mice persisted for several through peripheral expansion weeks on average without would be decreasing TCR dividing (Tough and Sprent, repertoire diversity with age. 1994). Two different The use of TRECs to define approaches were taken to undivided naive T cells presmeasure human naive T cell ents some uncertainties. As turnover. Michie et al. (1992) the authors discuss, the loss examined T cells from paof TRECs in human T cell poptients receiving therapeutic ulations over time may not irradiation and assayed for indicate cell division; instead, loss of cells with chromoit might indicate a failure to somal damage as a measure maintain extrachromosomal Figure 1. Diagram of TREC Content in Naive T Cell Populations of time between mitosis in DNA during the long life span The average TREC content of naive T cells remains comparable in both young T cells. Hellerstein and colof human naive T cells. and old mice. In humans, TREC content of T cells with naive phenotype leagues administered deuHowever, the results of den declines with age. terated water (2H2O) to Braber et al. do highlight the human subjects. The incorvast difference in scale poration of the 2H- isotope into replicating (TCR) genes during T cell development between human and mouse T cell life DNA was measured by mass spectrom- in the thymus. Because TRECs do not spans, indicating different mechanisms etry so that the fraction of labeled cells replicate during cellular proliferation in might exist to maintain T cells in humans could be determined (Neese et al., the periphery, the TREC content of T cell and mice. This suggests that the mouse 2002). Both of these studies found human populations correlates with thymic output may not always be a suitable animal model T cells to have an astonishing (to mouse assuming TRECs are stable. den Braber for a human. Several groups have worked immunologists) half-life on the order of et al. (2012) measure the average TREC to establish humanized mouse models in years instead of weeks. content in naive T cells of both mice and which human stem cells are used to reden Braber et al. (2012) repeat and humans. They find that naive T cells of constitute hematopoietic compartments extend these studies in both mice and mice have comparable TREC content of immunodeficient mice with human humans. They use deuterated water whether they are obtained from young immune cells. Mice with a human immune labeling to determine turnover of naive or old mice (Figure 1). In humans, in system would allow study of human T cells. In this study, the half-life of CD4+ contrast, the TREC content of T cells diseases such as HIV as well as allow and CD8+ T cell populations in mice was with naive phenotype is high in neonates study of environmental and cell-intrinsic determinants of T cell life span. How7 and 11 weeks, respectively. Earlier but declines with age. What might these findings mean? The ever, in humanized mice the naive T cell results from the same group indicated that human naive CD4+ T cells have an authors estimate the fraction of cells that turnover rate has been suggested to average half-life of 6 years, whereas were originally thymically derived using be even higher than the rate seen with CD8+ T cells have an average half-life of the average TREC content of the naive normal mouse T cells; the reasons for 9 years (Vrisekoop et al., 2008). Together, T cell population. Mathematical modeling this are not well understood (Legrand these results confirm the much shorter of the data indicates that up to 90% of et al., 2006). Another implication of this life span of naive T cells in mice compared human ‘‘naive’’ T cells are generated present study is that better markers are to humans. through proliferation in the periphery in needed to identify undivided naive T cells The different life spans of naive T cells in aged individuals. From these data, the in humans, given that many T cells presmice and humans might indicate distinct authors suggest that the mechanisms ently considered naive may have divided mechanisms to maintain naive T cell maintaining phenotypically naive T cells in the periphery. In mice, homeostatic populations. The authors examined the might be fundamentally different in mice proliferation of naive T cells generates relative contributions of naive T cell gen- and humans. Hence, thymic output main- cells functionally differing from naive eration by the thymus and T cell prolifera- tains naive T cell populations in mice, and T cells (Haluszczak et al., 2009). It is tion in the periphery. Similar to previous thymic involution and loss of thymic unknown whether human T cells proliferstudies, the authors quantified T cell output result in reductions in frequencies ating in the periphery with a naive phenoreceptor excision circles (TRECs) to de- of naive T cells in the periphery. In con- type are equivalent to naive T cells extermine thymic output (Douek et al., trast, human T cells may divide in the pe- ported from the thymus. Together, these 1998). TRECs are DNA byproducts of riphery without losing their naive pheno- data emphasize the need for improved somatic rearrangement of T cell receptor type on the basis of current markers. animal models and other tools to better 164 Immunity 36, February 24, 2012 ª2012 Elsevier Inc.
Immunity
Previews understand how human T cell populations are generated and maintained.
Dutilh, B.E., and de Boer, R.J. (2003). J. Theor. Biol. 224, 351–358.
Michie, C.A., McLean, A., Alcock, C., and Beverley, P.C. (1992). Nature 360, 264–265.
REFERENCES
Haluszczak, C., Akue, A.D., Hamilton, S.E., Johnson, L.D., Pujanauski, L., Teodorovic, L., Jameson, S.C., and Kedl, R.M. (2009). J. Exp. Med. 206, 435–448.
Neese, R.A., Misell, L.M., Turner, S., Chu, A., Kim, J., Cesar, D., Hoh, R., Antelo, F., Strawford, A., McCune, J.M., et al. (2002). Proc. Natl. Acad. Sci. USA 99, 15345–15350.
den Braber, I., Mugwagwa, T., Vrisekoop, N., Westera, L., Mo¨gling, R., de Boer, A.B., Willems, N., Schrijver, E.H., Spierenburg, G., Gaiser, K., et al. (2012). Immunity 36, this issue, 288–297. Douek, D.C., McFarland, R.D., Keiser, P.H., Gage, E.A., Massey, J.M., Haynes, B.F., Polis, M.A., Haase, A.T., Feinberg, M.B., Sullivan, J.L., et al. (1998). Nature 396, 690–695.
Kilpatrick, R.D., Rickabaugh, T., Hultin, L.E., Hultin, P., Hausner, M.A., Detels, R., Phair, J., and Jamieson, B.D. (2008). J. Immunol. 180, 1499–1507. Legrand, N., Cupedo, T., van Lent, A.U., Ebeli, M.J., Weijer, K., Hanke, T., and Spits, H. (2006). Blood 108, 238–245.
Tough, D.F., and Sprent, J. (1994). J. Exp. Med. 179, 1127–1135. Vrisekoop, N., den Braber, I., de Boer, A.B., Ruiter, A.F., Ackermans, M.T., van der Crabben, S.N., Schrijver, E.H., Spierenburg, G., Sauerwein, H.P., Hazenberg, M.D., et al. (2008). Proc. Natl. Acad. Sci. USA 105, 6115–6120.
Immunity 36, February 24, 2012 ª2012 Elsevier Inc. 165
Previews REFERENCES Dong, J., Ivascu, C., Chang, H.D., Wu, P., Angeli, R., Maggi, L., Eckhardt, F., Tykocinski, L., Haefliger, C., Mo¨wes, B., et al. (2007). J. Immunol. 179, 2389–2396. Hill, J.A., Feuerer, M., Tash, K., Haxhinasto, S., Perez, J., Melamed, R., Mathis, D., and Benoist, C. (2007). Immunity 27, 786–800. Hoffmann, P., Boeld, T.J., Eder, R., Huehn, J., Floess, S., Wieczorek, G., Olek, S., Dietmaier, W., Andreesen, R., and Edinger, M. (2009). Eur. J. Immunol. 39, 1088–1097. Klein, L., and Jovanovic, K. (2011). Semin. Immunol. 23, 401–409. Lio, C.W., and Hsieh, C.S. (2008). Immunity 28, 100–111. Miyao, T., Floess, S., Setoguchi, R., Luche, H., Fehling, H.J., Waldmann, H., Huehn, J., and Hori, S. (2012). Immunity 36, this issue, 262–275.
Figure 1. Commitment and Differentiation of Foxp3+ Treg Cells Differentiation of Treg cells along distinct pathways might be associated with a differential degree of commitment. Thymic development appears to be characterized by early commitment, even before expression of Foxp3, and preferential adoption of a stable phenotype that is imprinted by CpG demethylation in the TSDR (CNS2). Differentiation of Foxp3+ cells in the periphery includes a larger proportion of ‘‘promiscuous Foxp3+’’ cells that upregulate Foxp3 without acquisition of a stable suppressive phenotype, giving rise to both ‘‘exFoxp3’’ cells convertible into effector cells as well as to stable, peripherally induced Treg cells.
well as counteracting environmental signals and cell-intrinsic developmental predispositions. Answering of these questions will not only be of central importance for the
understanding of the origin of the Treg cell lineage, but also better define the conditions to be met when induction or expansion of Foxp3+ Treg cells for therapeutic application is intended.
Polansky, J.K., Kretschmer, K., Freyer, J., Floess, S., Garbe, A., Baron, U., Olek, S., Hamann, A., von Boehmer, H., and Huehn, J. (2008). Eur. J. Immunol. 38, 1654–1663. Rubtsov, Y.P., Niec, R.E., Josefowicz, S., Li, L., Darce, J., Mathis, D., Benoist, C., and Rudensky, A.Y. (2010). Science 329, 1667–1671. Schallenberg, S., Tsai, P.Y., Riewaldt, J., and Kretschmer, K. (2010). J. Exp. Med. 207, 1393– 1407. Zhou, X., Bailey-Bucktrout, S.L., Jeker, L.T., Penaranda, C., Martı´nez-Llordella, M., Ashby, M., Nakayama, M., Rosenthal, W., and Bluestone, J.A. (2009). Nat. Immunol. 10, 1000–1007.
Losing TREC with Age Shirley L. Zhang1 and Avinash Bhandoola1,* 1Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA *Correspondence: [email protected] DOI 10.1016/j.immuni.2012.02.005
In this issue of Immunity, den Braber et al. (2012) highlight differences in naive T cell lifespan between mice and humans. Their data suggest that mechanisms of naive T cell maintenance may differ between mice and men. How long do naive T cells live and how are they replenished? A short life span for naive T cells would necessitate faster rates of replenishment, whereas increased life span would accommodate
slower rates of replenishment. Work in this issue of Immunity by den Braber et al. (2012) examines the longevity of naive T cells. Their data suggest that mechanisms maintaining T cells with
naive phenotypes might differ in humans and mice (den Braber et al., 2012). The life span of mice is 2 years, whereas humans live much longer. Do the naive T cells of mice and humans
Immunity 36, February 24, 2012 ª2012 Elsevier Inc. 163
Immunity
Previews
also have different life spans? Such a possibility had been Tough and Sprent measured previously suggested in other T cell turnover in mice by human studies of naive T cells using bromodeoxyuridine (Dutilh and de Boer, 2003; (BrdU) treatment to label Kilpatrick et al., 2008). One dividing cells. These results consequence of maintaining indicated that naive T cells T cell populations chiefly in mice persisted for several through peripheral expansion weeks on average without would be decreasing TCR dividing (Tough and Sprent, repertoire diversity with age. 1994). Two different The use of TRECs to define approaches were taken to undivided naive T cells presmeasure human naive T cell ents some uncertainties. As turnover. Michie et al. (1992) the authors discuss, the loss examined T cells from paof TRECs in human T cell poptients receiving therapeutic ulations over time may not irradiation and assayed for indicate cell division; instead, loss of cells with chromoit might indicate a failure to somal damage as a measure maintain extrachromosomal Figure 1. Diagram of TREC Content in Naive T Cell Populations of time between mitosis in DNA during the long life span The average TREC content of naive T cells remains comparable in both young T cells. Hellerstein and colof human naive T cells. and old mice. In humans, TREC content of T cells with naive phenotype leagues administered deuHowever, the results of den declines with age. terated water (2H2O) to Braber et al. do highlight the human subjects. The incorvast difference in scale poration of the 2H- isotope into replicating (TCR) genes during T cell development between human and mouse T cell life DNA was measured by mass spectrom- in the thymus. Because TRECs do not spans, indicating different mechanisms etry so that the fraction of labeled cells replicate during cellular proliferation in might exist to maintain T cells in humans could be determined (Neese et al., the periphery, the TREC content of T cell and mice. This suggests that the mouse 2002). Both of these studies found human populations correlates with thymic output may not always be a suitable animal model T cells to have an astonishing (to mouse assuming TRECs are stable. den Braber for a human. Several groups have worked immunologists) half-life on the order of et al. (2012) measure the average TREC to establish humanized mouse models in years instead of weeks. content in naive T cells of both mice and which human stem cells are used to reden Braber et al. (2012) repeat and humans. They find that naive T cells of constitute hematopoietic compartments extend these studies in both mice and mice have comparable TREC content of immunodeficient mice with human humans. They use deuterated water whether they are obtained from young immune cells. Mice with a human immune labeling to determine turnover of naive or old mice (Figure 1). In humans, in system would allow study of human T cells. In this study, the half-life of CD4+ contrast, the TREC content of T cells diseases such as HIV as well as allow and CD8+ T cell populations in mice was with naive phenotype is high in neonates study of environmental and cell-intrinsic determinants of T cell life span. How7 and 11 weeks, respectively. Earlier but declines with age. What might these findings mean? The ever, in humanized mice the naive T cell results from the same group indicated that human naive CD4+ T cells have an authors estimate the fraction of cells that turnover rate has been suggested to average half-life of 6 years, whereas were originally thymically derived using be even higher than the rate seen with CD8+ T cells have an average half-life of the average TREC content of the naive normal mouse T cells; the reasons for 9 years (Vrisekoop et al., 2008). Together, T cell population. Mathematical modeling this are not well understood (Legrand these results confirm the much shorter of the data indicates that up to 90% of et al., 2006). Another implication of this life span of naive T cells in mice compared human ‘‘naive’’ T cells are generated present study is that better markers are to humans. through proliferation in the periphery in needed to identify undivided naive T cells The different life spans of naive T cells in aged individuals. From these data, the in humans, given that many T cells presmice and humans might indicate distinct authors suggest that the mechanisms ently considered naive may have divided mechanisms to maintain naive T cell maintaining phenotypically naive T cells in the periphery. In mice, homeostatic populations. The authors examined the might be fundamentally different in mice proliferation of naive T cells generates relative contributions of naive T cell gen- and humans. Hence, thymic output main- cells functionally differing from naive eration by the thymus and T cell prolifera- tains naive T cell populations in mice, and T cells (Haluszczak et al., 2009). It is tion in the periphery. Similar to previous thymic involution and loss of thymic unknown whether human T cells proliferstudies, the authors quantified T cell output result in reductions in frequencies ating in the periphery with a naive phenoreceptor excision circles (TRECs) to de- of naive T cells in the periphery. In con- type are equivalent to naive T cells extermine thymic output (Douek et al., trast, human T cells may divide in the pe- ported from the thymus. Together, these 1998). TRECs are DNA byproducts of riphery without losing their naive pheno- data emphasize the need for improved somatic rearrangement of T cell receptor type on the basis of current markers. animal models and other tools to better 164 Immunity 36, February 24, 2012 ª2012 Elsevier Inc.
Immunity
Previews understand how human T cell populations are generated and maintained.
Dutilh, B.E., and de Boer, R.J. (2003). J. Theor. Biol. 224, 351–358.
Michie, C.A., McLean, A., Alcock, C., and Beverley, P.C. (1992). Nature 360, 264–265.
REFERENCES
Haluszczak, C., Akue, A.D., Hamilton, S.E., Johnson, L.D., Pujanauski, L., Teodorovic, L., Jameson, S.C., and Kedl, R.M. (2009). J. Exp. Med. 206, 435–448.
Neese, R.A., Misell, L.M., Turner, S., Chu, A., Kim, J., Cesar, D., Hoh, R., Antelo, F., Strawford, A., McCune, J.M., et al. (2002). Proc. Natl. Acad. Sci. USA 99, 15345–15350.
den Braber, I., Mugwagwa, T., Vrisekoop, N., Westera, L., Mo¨gling, R., de Boer, A.B., Willems, N., Schrijver, E.H., Spierenburg, G., Gaiser, K., et al. (2012). Immunity 36, this issue, 288–297. Douek, D.C., McFarland, R.D., Keiser, P.H., Gage, E.A., Massey, J.M., Haynes, B.F., Polis, M.A., Haase, A.T., Feinberg, M.B., Sullivan, J.L., et al. (1998). Nature 396, 690–695.
Kilpatrick, R.D., Rickabaugh, T., Hultin, L.E., Hultin, P., Hausner, M.A., Detels, R., Phair, J., and Jamieson, B.D. (2008). J. Immunol. 180, 1499–1507. Legrand, N., Cupedo, T., van Lent, A.U., Ebeli, M.J., Weijer, K., Hanke, T., and Spits, H. (2006). Blood 108, 238–245.
Tough, D.F., and Sprent, J. (1994). J. Exp. Med. 179, 1127–1135. Vrisekoop, N., den Braber, I., de Boer, A.B., Ruiter, A.F., Ackermans, M.T., van der Crabben, S.N., Schrijver, E.H., Spierenburg, G., Sauerwein, H.P., Hazenberg, M.D., et al. (2008). Proc. Natl. Acad. Sci. USA 105, 6115–6120.
Immunity 36, February 24, 2012 ª2012 Elsevier Inc. 165