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The Journal of Immunology, 1999, 163: 1253-1257.
Copyright © 1999 by The American Association of Immunologists

On the Lifespan of Virgin T Lymphocytes

Francesca Di Rosa1,*, Sridhar Ramaswamy{dagger}, John P. Ridge* and Polly Matzinger*

* Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and {dagger} Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
To study the lifespan of virgin T lymphocytes, we removed the thymus from adult female mice and then, at various times afterward, tested their ability to mount an immune response to a newly encountered Ag, the male Ag H-Y. We found that unprimed thymectomized mice were able to generate a primary response to H-Y for some time after thymectomy but lost this ability at ~6 mo. In contrast, mice that were primed to H-Y just after thymectomy continued to display immunological memory to H-Y for >1 year. These experiments show that primary immune responses disappear in the absence of a thymus.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
The question of whether naive T cells have a defined and limited lifespan has been around for some time (1). Starting in 1965, several groups used adult thymectomy to stop the influx of naive T cells and studied the subsequent peripheral decay of T cell responses (2, 3, 4, 5). In general, they found that the responses dropped but did not disappear. More recently, other groups transferred naive T cells into immunoincompetent hosts (6, 7). Again, they found that the naive pool is self-sustaining, although there was no cell division in the absence of Ag (8). The conclusion has been that a naive T cell has no intrinsic limit to its lifespan and that therefore, to prevent an overload of the available space in the face of continuous thymic production, the numbers of naive T cells might be held constant by competition for space or "niches" (9, 10).

We decided to re-examine the question of lifespan for several reasons. First, we were uncertain about some of the Ags used in the previous studies. T cells are more cross-reactive than previously realized (11, 12, 13, 14). Thus, many "primary" immunizations might also stimulate a subset of memory cells, previously primed by a cross-reactive environmental Ag. This might account for the patterns seen after thymectomy, where the responses dropped to a certain level (due to the loss of naive cells?) but did not disappear (due to the persistence of the subset of cross-reactively primed memory cells).

Second, we were uncertain about some of the T cells. For example, studies done with TCR transgenic (Tg)2 T cells have often been confounded by the finding that Tg T cells often express a second endogenous TCR {alpha}-chain (15) that may respond to environmental Ags and thus allow the persistence of cells that would otherwise die for lack of Ag stimulation (9, 16). In a few cases, the persistence of naive T cells was studied in Tg mice crossed to a RAG-/- background, in which no endogenous TCR chains are made. Although the Ag in this case, H-Y, was appropriate because it does not appear to have significant environmental cross-reactants (17, 18, 19), persistence was followed for no longer than 8–9 wk (20, 21, 22, 23).

In 1965, Taylor noticed that the alloresponses of thymectomized mice remained unchanged for ~26 wk (2), after which they began to drop. Therefore, we studied the persistence of responses to H-Y in normal C57BL/6 (B6) mice for a period of >1 year. In three separate experiments done over a period of 5 years, we found that thymectomized mice completely lost the ability to mount a primary cytotoxic response to H-Y at ~6 mo postthymectomy, whereas their memory response to the same Ag was unaffected. From this, we conclude that naive cells cannot live indefinitely in the absence of their cognate Ag.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Mice

B6, AKR, and CBA/J mice (6–8 wk old) from Taconic Laboratories (Germantown, NY) or Clarence Reeder (National Cancer Institute, Frederick, MD) were housed at the National Institute of Allergy and Infectious Diseases, accredited by the American Association for Accreditation of Laboratory Animal Care.

Adult thymectomy

For series I, we thymectomized the B6 female mice. We anesthetized the mice with 0.3–0.5 ml of Avertin and made a supra clavicular incision of skin followed by blunt dissection of throat muscle; next, we inserted a blunt suction pipette and removed each individual lobe of the thymus by applying suction. Age-matched controls were similarly sham-thymectomized without removing the thymus. For series II and III, we purchased B6 female mice that had been thymectomized at 6–8 wk of age at Taconic Laboratories.

Abs and cytofluorometric analysis

We stained for TCR-, CD4-, CD8-, and CD44-positive cells with anti-TCR-FITC (H57, PharMingen, San Diego, CA), anti-CD4-PE or -APC (RM4-4, PharMingen), anti-CD8{alpha}-Red 613 or -PE (53-6.7, Life Technologies, Grand Island, NY), and anti-CD44-FITC or -PE (Pgp-1, IM7, PharMingen) mAbs, followed by analysis with a FACScan or FACScalibur (Becton Dickinson, San Jose, CA). Each sample was first incubated with the anti-Fc{gamma}R mAb (2.4G2, American Type Culture Collection, Manassas, VA) (24) to block nonspecific staining.

In vivo immunization

B6 female mice were immunized by an i.p. injection of 2 x 106 B6 male splenocytes prepared in PBS.

Cytotoxicity tests

Spleen cells from each responder mouse were stimulated in vitro with syngeneic (B6) male or allogeneic (AKR or CBA/J) female spleen cells and tested 5 days later for killing activity by the JAM test (25). Briefly, 4–6 x 106 responder spleen cells were cultured for 5–6 days against 2 x 106 irradiated (1500–3000 rad) stimulator spleen cells in 2 ml of IMDM supplemented with 10% FCS, 50 U/ml penicillin, 50 µg/ml streptomycin sulfate, 50 µg/ml gentamicin sulfate, 4 mM glutamine, and 50 µM 2-ME. At the end of the 5- to 6-day culture, the responders were harvested and tested for cytotoxic activity against [3H]thymidine-labeled B6 male, AKR, CBA/J, or B6 female Con A-activated spleen cell blasts. In some experiments, the cultures were performed either with or without optimal concentrations of conditioned supernatant (rat T-Stim without Con A, Collaborative Biomedical Products, Bedford, MA) as a source of helper factors.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
Phenotype of cells in young, aged, and thymectomized mice

Fig. 1Go shows the numbers and CD44 distribution of T cells in the spleens of normal and thymectomized mice. Like Swain et al. (26), we found that normal aging mice maintained fairly stable numbers of CD44negative/low "naive" cells. This could be due to two factors. Either 1) the thymic output of naive cells compensates for losses due to death or to activation of naive cells and their subsequent movement into the memory pool, or 2) some CD44high cells revert to a CD44negative/low phenotype. To discriminate between these two possibilities, we looked at thymectomized mice and found that the naive CD44negative/low cells disappear with time, whereas the CD44high "memory" pool remains relatively unchanged. Thus, although there may be a certain amount of conversion from CD44high to CD44negative/low, it is not sufficient to maintain the pool in the absence of a thymus.



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  		FIGURE 1. Number of CD4, CD8, and CD44 cells in the spleens of control and thymectomized (Tx) mice. B6 female mice were either thymectomized or sham-thymectomized at 6 wk of age and analyzed after 26 wk. Spleen cells from 6- to 12-wk-old and 10-mo-old normal control mice, thymectomized mice, and sham-thymectomized mice were counted, stained with mAbs to CD4, CD8, and CD44, and analyzed by FACS. Total numbers of CD4+ or CD8+ CD44high and CD4+ or CD8+ CD44negative/low spleen cells are shown. The total numbers of cells in the spleen are indicated on the top of each column in the CD4 cell graph.

 
Virgin responses to H-Y

To determine whether the loss of naive cells in thymectomized mice was due to death or movement to the memory pool, we measured the responses of these mice to H-Y. If naive T cells are becoming memory cells, they should respond well to an injection of male cells; however, if the naive T cells are dying, there should come a point at which they would no longer be able to respond.

In the first series of experiments, we thymectomized or sham-thymectomized 40 B6 female mice at 6 to 8 wk of age. At various times afterward, we immunized three to five mice from each group against B6 male spleen cells and tested them 3 wk later for anti-H-Y killing activity after a secondary stimulation culture in vitro. Fig. 2GoA shows that the ability to be primed began to wane at 22 wk; by 26 wk postthymectomy, the thymectomized mice were almost completely unresponsive to H-Y.



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  		FIGURE 2. Over time, virgin thymectomized female mice lose the ability to mount a cytotoxic response to H-Y. A, Series I: adult thymectomized and sham-thymectomized B6 female mice were injected i.p. with 2 x 106 B6 male spleen cells at different times postthymectomy and tested 3 wk later. Responder spleen cells were cultured for 5 days in vitro against B6 male stimulators and subsequently tested for killing against B6 male and B6 female targets. For each timepoint, the killing of cells from individual mice on male targets is shown. The killing on female targets averaged no higher than 7%. B, Series II: age-matched mice were thymectomized at 6–8 wk and subsequently primed at different times postthymectomy. Series III: mice were thymectomized at different times and tested on the same day. In both series, responder spleen cells were cultured against male stimulators for 5 days in vitro in cultures containing conditioned supernatant as a source of helper factors and subsequently tested for anti-H-Y killing on B6 male and female targets. For each timepoint, the killing of cells from single mice on male targets is shown. The killing on female targets averaged no higher than -1% for the second series and 12% for the third series of experiments. In both A and B, the numbers of weeks postthymectomy (pTx) are indicated on the top of each panel.

 
To determine whether thymectomized mice might contain a small number of persisting anti-H-Y CTLs that did not respond because of decreased IL-2 production by Th cells from aged mice (27), we tested a second series of mice in which we added a source of helper factors to the in vitro tests. To control for variability between assays performed on different days, we created a third series that consisted of mice thymectomized at different times, immunized altogether, and tested on the same day. In these two series, the control mice were left unthymectomized rather than sham-thymectomized to control for a potential rebound from lymphocyte loss resulting from the trauma of thymectomy. Fig. 2GoB shows that the virgin response to H-Y decayed in both groups of thymectomized mice and was no longer detectable by 36 wk postthymectomy, even in assays in which help was not limiting and in experiments with two different schedules. These data confirmed that, with time, thymectomized B6 female mice lose the ability to develop a primary anti-H-Y response.

Memory responses to H-Y

To investigate whether thymectomy affects memory responses to H-Y, we primed normal and thymectomized mice at 5 wk postthymectomy and tested three to five females from each group at 16, 34, and 54 wk postthymectomy. Fig. 3GoA shows that these mice still responded strongly 1 year later. These results suggest that although primary responses to H-Y wane after thymectomy, memory responses do not.



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  		FIGURE 3. The anti-H-Y cytotoxic memory response remains high in thymectomized mice. Adult thymectomized and age-matched normal B6 female mice were injected i.p. with 2 x 106 B6 male spleen cells at 5 wk postthymectomy and tested at different times afterward. The numbers of weeks postthymectomy (pTx) are indicated on the top of each panel. A, Responder spleen cells were cultured for 5 days in vitro against B6 male stimulators and subsequently tested for killing against B6 male and female targets. B, The same responders as in A, cultured against CBA/J female stimulators and subsequently tested for killing against CBA/J or B6 female targets. For each timepoint, the killing is shown of cells from a single mouse on B6 male and CBA/J female targets. The killing on B6 female targets averaged no higher than 3%.

 
Alloresponses

Because the response against allogeneic MHC is directed against a wide variety of peptide/MHC complexes (28, 29), some of the responding cells may be preprimed by cross-reactive Ags. The naive portion of the response should therefore wane in thymectomized mice while the memory portion remains intact. Fig. 3GoB shows that the anti-CBA/J alloresponses of the B6 thymectomized mice began to drop at ~34 wk postthymectomy; three of five thymectomized mice had a very weak anti-CBA/J response at 1 year. The variability in decay among individual thymectomized mice in a group might depend upon differences in their immunological history. Each mouse maintains its own idiosyncratic pool of memory cells (13, 30), which might cross-react or not against allogeneic MHC molecules (11, 12).

Thymus output and aging

Fig. 4GoA is a summary of 128 mice tested in three independent series of experiments. Like Taylor (2), we found that the virgin response remained steady for the first 4–5 mo and then rapidly declined. Although anti-MHC responses were still visible, the anti-H-Y response disappeared entirely. The response also declined in normal, unthymectomized mice; however, more than half of these mice remained responsive at the 1-yr timepoint, suggesting that the thymus continues to contribute to the primary responses of 1-yr-old normal mice. Fig. 4Go, B and C plot the means of the responses from each 5-wk time period postthymectomy, showing that memory responses to H-Y did not decline; anti-allo-MHC responses showed only a small decay in both thymectomized and control groups.



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  		FIGURE 4. Summary. A, Anti-male responses from mice primed at various times postthymectomy. In three independent series of experiments, adult thymectomized (Tx) and age-matched control B6 female mice were either untreated or injected i.p. with 2 x 106 B6 male spleen cells at different times postthymectomy. Responder spleen cells were cultured for 5 days in vitro against B6 male stimulators and subsequently tested for killing against B6 male and female targets. Primed mice are the same as in Fig. 2Go, and only the results obtained from cultures in the absence of conditioned supernatant are shown here. For each series, the killing of single mice on male targets is shown at the responder:target ratio at which the curve drops off the plateau. B, We grouped the tests from Figs. 2–4GoGoGo into short intervals of 5 wk postthymectomy and took the averages to obtain an overview of the response levels over time. C, We grouped all the tests against allogeneic, MHC-desperate cells as in B to obtain an overview.

 
Concluding remarks

Our data support the first part of a recently suggested scenario in which the virgin and memory T cell pools are independently regulated (31). However, they do not support the second suggestion, that virgin cells have an indefinite lifespan and that the numbers are regulated by a finite number of niches for which circulating naive cells and newly emerging thymocytes compete (9, 10). This view predicts that, if the thymus is removed, the naive cells should last indefinitely at the number set by the number of niches. We found that naive T cells do not have an infinite lifespan (although it is surprisingly long), and that the thymus itself is important to the survival of the naive cell pool. Without it, the pool disappears, both phenotypically and functionally.

How then do normal aging individuals maintain the ability to respond to new Ags? There are at least two possibilities. First, the thymus does not involute completely. Although its output drops in the mouse from 2 x 106/day at 8 wk to 1 x 105/day at 6 mo (32, 33), it continues to export T cells. If any of these cells are new naive T cells, this could contribute 18 million T cells every 6 mo to replace those that are dying. The thymus might also put out soluble factors that contribute to the survival of naive T cells.

Second, memory cells may be far more flexible than is normally supposed. Cross-reactions abound (11, 12, 13, 14). Selin et al. (13) showed that a small proportion of T cells to one virus can be moved to the memory compartment by priming with an unrelated virus, and many cross-reactions have been seen between one peptide/MHC complex and another (11, 12, 34). Thus, the appearance of a new Ag might stimulate cross-reactive memory T cells. Although the primary response to individual peptides (such as H-Y) may disappear with time, most pathogens present a multitude of Ags. Thus, even if the thymus eventually stops producing, the variety of cross-reactive receptors maintained in the memory pool should allow for responsiveness to a wide range of new antigenic challenges.

Finally, why should a thymectomized mouse respond well for months and then suddenly lose this ability? Such a pattern suggests that two interacting cells are approaching limiting numbers at about the same time (35); this possibility fits nicely with our current understanding of Th-CTL interactions, in which it appears that Th cells "educate" APCs and thereby enable them to activate CTL precursors (36, 37, 38). Immediately after thymectomy, there are enough helpers to educate all of the H-Y-presenting APCs. As the number of T cells decreases, the probability that an APC will encounter a helper before it meets a killer will drop. However, the few that do will initiate a response and the drop in frequency will not be noticed. Eventually, the number of T cells will have declined enough so that no APC meets both a helper and a killer and no response can occur. Thus, the response disappears before the last responding cells have died. Our estimate of the lifespan of an H-Y-specific T cell is thus likely to be a slight underestimate. It is nevertheless surprisingly long. Six months is about one quarter of the life of a mouse. It will be interesting to see whether the lifespan of naive T cells in longer-lived species is corresponding lengthened.


   Acknowledgments
 
We thank Albert Bendelac, Ron Germain, Ron Schwartz, and Corinne Tanchot for reading the manuscript. We also thank Ron Schwartz for supporting a creative environment.


   Footnotes
 
1 Address correspondence and reprint requests to Dr. Francesca Di Rosa at the current address: Laboratorio di Fisiopatologia, Centro Ricerca Sperimentale, Istituto Regina Elena via delle Messi d’Oro, 156, 00158 Rome, Italy. E-mail address: Back

2 Abbreviations used in this paper: Tg, transgenic, B6, C57BL/6. Back

Received for publication March 3, 1999. Accepted for publication May 20, 1999.


   References
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 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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