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Cutting Edge: Cytolytic Effector Function in Human Circulating CD8⁺ T Cells Closely Correlates with CD56 Surface Expression¹

Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland

	Abstract

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Recent data suggest that human effector CD8⁺ T cells express a distinct CD27^-CD45RA^high (CD57⁺CD28^-CD11a^high) phenotype. Here, we propose that CTL effector function correlates better with CD56 (neuronal cell adhesion molecule (NCAM)) surface expression. CD56 was absent on cord blood CD8⁺ T cells, but was expressed by 4–30% of freshly isolated circulating CD8⁺ T cells from 15 adults. Dramatic oligoclonal expansions in 3/3 individuals were confined to the CD56⁺ subset of CD8⁺ T cells. The CD56⁺ subset generally contained high amounts of intracellular perforin and granzyme B. Finally, direct cytolytic capacity was closely restricted to the CD56⁺(CD45RA^high) cells, better than to CD27^-CD45RA^high cells in 5/5 individuals analyzed. Thus, the phenotype corresponding to the circulating effector CD8⁺ T cell pool may be simplified and more precisely defined by the use of just two surface markers: CD8 and CD56.

	Introduction

Top Abstract Introduction Materials and Methods Results and Discussion References

 
The CTL-mediated immune response plays an essential role in the protection of the host against infectious diseases and cancer. Ag recognition by naive CD8⁺ T cells triggers a program of proliferation and differentiation that leads to the production of effector lymphocytes directly able to lyse Ag-bearing cells. The lytic mechanism primarily involves release of cytoplasmic granules loaded with perforin (a pore-forming protein) and granzyme B (a serine protease) at the contact site between CTL and target cell (1, 2). To maintain homeostasis, a large fraction of Ag-specific CTL are eliminated thereafter. Some cells differentiate into so-called memory cells that are not directly cytolytic but can be rapidly reactivated upon exposure to Ag (3).

A precise phenotyping for the different functional stages of CTL, from naive to memory, has become essential to study in detail and monitor in vivo immune responses. In humans, the CD45RA and CD45RO surface Ags have been used to separate T cells into naive and memory pools, respectively. The CD45RA^low/RO⁺ fraction selectively recognizes recall Ags in vitro (4), contains elevated frequencies of Ag-specific precursors (5), and presents low stringency activation requirements (6). However, discrimination between naive and memory states based only on CD45 isoform expression is insufficient since, with time, some CD45RO T cells may revert to CD45RA (7), and a fraction of CD45RA^high cells presents phenotypic features of primed cells (8, 9). A large proportion of effector CD8⁺ T cells that exert direct cytolytic function and contain intracellular perforin and granzyme B are CD28^- (10, 11, 12), CD57⁺ (13, 14) or CD11a^high (15). Recently, it has been observed that CD45RA^high cells previously proposed to define the naive CD8⁺ T cell pool may indeed contain both naive and effector lymphocytes, and that both populations may be discriminated based on CD27 surface expression (16, 17, 18). CD27^-CD45RA^high cells, which display the phenotypic and functional properties of effector CD8⁺ T cells, generally present a CD28^-CD57⁺CD11a^high phenotype (16), confirming the previous phenotypes attributed to cytolytic lymphocytes (10, 11, 12, 13, 14, 15). Hence effector lymphocytes may express a distinct CD27^-CD45RA^high phenotype as compared with naive (CD27⁺CD45RA^high) or memory (CD27⁺CD45RA^low) CD8⁺ T cells.

In preliminary experiments we observed that some CD27^-CD45RA^high cells were not cytolytic. Furthermore, we found that a subpopulation of activated CD8⁺ T cells up-regulated CD56 (neuronal cell adhesion molecule (NCAM)³). To further characterize the functional properties of various CD8⁺ T cell populations, we sorted the cells based on the expression of CD27, CD45RA, and CD56. Our results clearly indicate that CD56⁺ cells, which are generally but not always CD45RA^high, better demarcate a subset with the properties of effector lymphocytes, as compared with the previously proposed CD27^-CD45RA^high cells.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Preparation of T lymphocytes

Human mononuclear cells from peripheral blood of healthy donors (HD) (Blood Transfusion Center, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland) and from cord blood (Maternity Service, CHUV, Lausanne) were separated and cryopreserved as previously described (19). For certain experiments, CD8^bright cells were highly enriched (>98% TCR/ß⁺CD3⁺CD8⁺) from PBMC by two rounds of positive selection using the MiniMACS system (Miltenyi Biotec, Sunnyvale, CA) (19). The procedure did not detectably alter the phenotype of CD8⁺ T cells (M. J. Pittet and P. Romero, unpublished results).

Phenotypic analyses

All mAbs were obtained from Becton Dickinson (Mountain View, CA), except anti-CD45RO^PE (DAKO, Denmark); anti-CD28^FITC, all anti-TCR Vß, and V24 (Immunotech, Marseille, France); streptavidin^Tricolor (Caltag, Burlingame, CA); anti-perforin^FITC (Ancell, Bayport, MN); and anti-granzyme B^FITC (Hölzel Diagnostica, Köln, Germany). For cell surface staining, cells (5 x 10⁵) were incubated for 20 min at 4°C with mAbs in 50 µl of PBS/2% BSA/0.2% azide. For intracellular staining, cells were first stained with cell surface mAbs as described, washed, and then fixed and permeabilized in 1 ml Orthopermeafix (Ortho Diagnostic Systems, Raritan, NJ) for 40 min at room temperature, washed twice, and incubated with intracellular mAbs for 40 min at 4°C. Cells were then washed and immediately analyzed on a FACScalibur. Data acquisition and analysis was performed using CellQuest software.

Ex vivo cytolytic assays

MiniMACS-enriched CD8⁺ T cells were sorted into defined fractions on a FACStar and then cultured overnight in RPMI 1640 10% FCS supplemented with 0.55 mM Arg, 0.24 mM Asn, 1.5 mM Gln, and 10 mM HEPES buffer. Cytolytic activity was tested in an anti-CD3 mAb redirected ⁵¹Cr release assay. Fc receptor-bearing P815 target cells were labeled with Na⁵¹CrO₄ for 1 h at 37°C. Lymphocytes from the defined sorted fractions were added to 1000 labeled P815 target cells at various lymphocyte/target cell ratios (L:T = 0.3, 1, 3, 10, and eventually 30). After incubation for 4 h at 37°C in the presence or absence of anti-CD3 mAb (LAUT3, 300 ng/ml), supernatants of duplicate cultures were collected and counted in a gamma counter. The percentage of target cell lysis was calculated as previously described (19).

	Results and Discussion

Top Abstract Introduction Materials and Methods Results and Discussion References

 
CD56 surface expression on circulating CD8⁺ T cells

PBMC from 15 healthy adults were analyzed ex vivo by flow cytometry. Cells exhibiting a CD27^-, CD28^-, or CD57⁺ phenotype, previously attributed to effector lymphocytes (10, 11, 12, 13, 14, 15, 16, 17, 18), represented 10–70% (mean, 30%; SD, 16%) of the CD8⁺ T cell pool (Fig. 1). The sizes of each fraction were very similar and highly correlated in single individuals (p < 0.001, linear regression analysis), consistent with the previous use of these markers to define the same functional population (10, 16, 20). In contrast, CD56 was found on the surface of only 4–30% of CD8⁺ T cells (mean, 15%; SD, 8%). Using simultaneous staining with anti-CD56, -CD57, and -CD45RA mAbs, we found that, on average, two thirds of CD56⁺ cells were also CD57⁺ (mean, 62%; SD, 22%) and CD45RA^high (mean, 65%; SD, 14%), compatible with effector CD8⁺ lymphocytes. However, about one-third of CD56⁺ cells exhibited an alternative phenotype.

View larger version (19K): [in this window] [in a new window]   FIGURE 1. Enumeration of the CD27-, CD28-, CD56+, and CD57+ fractions within the CD8+ T cell pool in 15 adults. Ex vivo PBMC were simultaneously stained with either CD27PE, CD28PE, or CD56PE in combination with CD8PerCP and APC-labeled CD57 mAbs. Live lymphocytes were further gated on CD8bright (>98% TCRß+CD3+CD8+) cells.

CD56⁺ CD8⁺ T cells display dramatic oligoclonal expansions

Previous reports have shown expansions of CD8⁺ T cells expressing specific TCR V gene segments in the CD27^- (18), CD57⁺ (13, 21), or CD28^- (22) fractions. We examined the distribution of Vß segments in the CD56^- and CD56⁺ fractions of CD8⁺ T cells from three individuals (repertoire of HD 001 and 329 in Fig. 2) using mAbs directed against 21 different Vß subfamilies that cover 60% of the TCR repertoire. Relatively large expansions (>10%) of CD8⁺ T cells were selectively found in the CD56⁺ fraction in all three individuals (HD 001: Vß 12, 14 and 16 ; HD 004: Vß 2, 14, 17 ; HD 329: Vß 14) with little or no representation of the other Vß. Although the oligoclonally expanded CD8⁺ T cells from HD 001 and 004 presented an expected CD27^- phenotype (18), those from HD 329 were CD27⁺ (not shown). Hence, the oligoclonal expansions in all three individuals were always found in CD56⁺ lymphocytes. This is consistent with the CD56⁺ phenotype being a candidate marker for effector CD8⁺ T cells stimulated by random Ags in vivo. Furthermore, CD56⁺ CD8⁺ T cells were always V24^-Vß11^- (not shown), and thus did not correspond to NKRP1A⁺ NKT cells (23, 24).

View larger version (21K): [in this window] [in a new window]   FIGURE 2. Vß expression in CD8+ T cell subsets from individuals HD 001 (upper panel) and 329 (lower panel). Ex vivo PBMC were stained with FITC-labeled Vß-specific mAbs in combination with CD56PE and CD8PerCP mAbs. Cells were gated on CD8bright (>98% TCRß+CD3+CD8+) cells.

The direct cytolytic capacity of effector lymphocytes ex vivo is primarily due to pore-forming proteins (perforin) and serine proteases (granzymes) contained within cytoplasmic granules and released into the vicinity of target cell membranes, thus triggering apoptosis (1, 2). We assessed by flow cytometry the presence of perforin and granzyme B in various subsets of freshly isolated CD8⁺ T cells. Both perforin⁺ and granzyme B⁺ CD8⁺ T cells from individuals HD 001 and 329 were highly enriched in the CD56⁺ subset but were not always restricted to CD27^- cells (Fig. 3). The use of PBMC from other individuals (HD 099, 101) also confirmed that intracellular accumulation of mediators of cytotoxicity was highly enriched in the CD56⁺ pool (not shown). As exceptions, perforin⁺ and granzyme B⁺ cells from HD 108 were only poorly enriched in the CD56⁺CD27^- subset and also found in the CD56^-CD27⁺ subset, and those from HD 421 were mainly CD56^-CD27⁺ (not shown). Thus, in most cases (at least 4/6 individuals), CD56⁺ CD8⁺ T cells contained high amounts of perforin and granzyme B and may correspond to functional effector lymphocytes.

View larger version (35K): [in this window] [in a new window]   FIGURE 3. Intracellular content of perforin and granzyme B in CD8+ T cell subsets from individuals HD 001 and 329. Purified CD8+ T cells were stained with either CD56PE and CD45RACyc or CD56Cyc and CD27PE mAbs, fixed and permeabilized, then stained with either anti-perforinFITC or anti-granzyme BFITC mAbs. The distribution of (A) perforin+ or (B) granzyme B+ cells (black dots) is shown among the total CD8+ T cell population (gray dots).

To directly assay the cytolytic capacity of effector lymphocytes, ex vivo purified and two color stained CD8⁺ T cells were sorted into defined fractions and tested in anti-CD3 mAb redirected cytolytic assays (Fig. 4). Initially, CD8⁺ T cells from individuals HD 001, 004, and 108 were sorted according to their CD56/CD45RA phenotypes (data for HD 004 in Fig. 4, A and B). Although CD56^- cells (i.e., both CD56^-CD45RA^high and CD56^-CD45RA^low fractions) exhibited very low cytolytic activity, CD56⁺ cells potently killed the targets in all three donors analyzed. Within CD56⁺ cells, the cytolytic activity was always extremely high for CD45RA^high cells, and undetectable to intermediate for CD45RA^low cells (at best 10 times lower than in the CD45RA^high fraction for HD 001, not shown). Thus, functional effectors in these three individuals were confined to the CD56⁺ (CD45RA^high) pool. Nevertheless, it cannot be excluded that CD56⁺CD45RA^low lymphocytes, which on average represent one-third of CD56⁺ cells, may also account for some cytolytic activity in several individuals.

View larger version (33K): [in this window] [in a new window]   FIGURE 4. Ex vivo cytolytic activities of CD8+ T cell subsets from individuals HD 004, 108, and 329. Purified CD8+ T cells were sorted into the indicated subsets (A, C, and E). The populations labeled "all" represent purified CD8+ T cells that were treated with the same Abs, passed through the FACS, but not sorted. Cytotoxicity against FcR+ P815 target cells was analyzed after overnight culture at various L:T ratios in the presence of CD3 mAb in a 4-h 51Cr release assay (B, D, and F). All sorted populations were unable to lyse P815 cells in the absence of CD3 mAb (not shown). Results are the mean of duplicate cultures.

To further assess the phenotype of ex vivo cytolytic populations, CD8⁺ T cells from individuals HD 108, 242, and 329 were sorted according to their CD56/CD27 phenotypes. It is worth noting that, within CD27^- cells, only the CD56⁺ but not the CD56^- cells from HD 108 (Fig. 4, C and D) and from HD 242 (not shown) exerted cytolytic activity in independent experiments. In contrast to these individuals (HD 108 and 242), the CD56⁺ cells from HD 329 were preferentially CD27⁺. Therefore, we also tested the subpopulations of this donor. Interestingly, only CD56⁺CD27⁺ cells exerted potent cytolytic activity, whereas the CD56^-CD27^- cells did not (Fig. 4, E and F). Hence, functional data on ex vivo PBMC from 5 of 5 individuals strongly suggest that CD56⁺, which are generally but not always CD45RA^high cells, better parallel the direct cytolytic properties of effector lymphocytes, rather than the previously described CD27^-CD45RA^high pool.

Concluding remarks

The CD56 Ag (NCAM) is a membrane glycoprotein belonging to the Ig superfamily. In humans, CD56 represents a prototypic marker of NK cells and is also found on a subset of CD4⁺ and CD8⁺ T cells. NK and T cells predominantly express a 140-kDa isoform product of CD56, which contains six potential sites for N-linked glycosylation extensively modified with polysialic acid. CD56 is a homotypic ligand. Neither its biochemical activity nor cellular function have been identified.

We propose here that expression of CD56 on CD8⁺ T cells is a marker for the currently effector-circulating lymphocytes since 1) they are nearly absent in cord blood, 2) they display diverse dramatic oligoclonal expansions in adults, 3) the percentage of CD56⁺ CD8⁺ T cells in a given individual can change by a factor of more than three within a few days (not shown), 4) CD56⁺ CD8⁺ T cells generally contain high amounts of intracellular perforin and granzyme B, and 5) direct cytolytic activity is closely restricted to CD56⁺ CD8⁺ T cells.

The correlation between cytolytic function and CD56 expression was remarkably high, since only very weak or no lytic activity was found in the CD56^- populations studied. In contrast, the correlation of CD56 expression with intracellular content of perforin and granzyme B was less tight, which matches the observation that expression of these mediators and cytotoxicity are not tightly linked (1, 2).

In accordance with the presence of an effector subset in vivo, previous studies have reported elevated numbers of CD57⁺ CD8⁺ T cells in several clinical situations (13, 14, 25, 26, 27). However, this population also represents a high proportion of CD8⁺ T cells in healthy adult individuals (10–70%). In this study, by defining effector cells with the CD56⁺ phenotype (instead of CD27^- or CD57⁺), its size is reduced to 4–30% of CD8⁺ T cells. Nevertheless, detectable amounts of CD56⁺ CD8⁺ T cells found in all 15 donors analyzed in this study imply that effectors may continuously be present in the circulation, representing a nonnegligible proportion of CD8⁺ T cells.

The capacity of lysis of CD56⁺ effector lymphocytes may however be reduced by inhibitory functions in vivo. For instance, it has been shown that CD8⁺ T cells expressing NK receptors (NKR) are enriched within the CD28^-CD57⁺ fraction (28, 29) and that tumor-specific CTL found in some cancer patients present a CD28^-CD57⁺NKR⁺ phenotype in vivo (30). Since the majority of CD56⁺ cells are generally found within the CD57⁺ subset, CD8⁺ T cells that express NK receptors could represent an important fraction of the CD56⁺ pool.

Based on the tight association between cytolytic effector function and CD56 expression demonstrated in this study, we propose that CD56 represents a useful marker to identify and monitor effector CD8⁺ T cells in different clinical situations.

	Acknowledgments

 
We thank Pierre Zaech for excellent technical assistance.

	Footnotes

 
¹ This work was supported in part by Grant KFS 633-2-1998 from the Swiss Cancer League.

² Address correspondence and reprint requests to Dr. Pedro Romero, Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Centre Hospitalier Universitaire Vaudois, BH 19-602, 1011 Lausanne, Switzerland. E-mail address:

³ Abbreviations used in this paper: NCAM, neuronal cell adhesion molecule; HD, healthy donor; L:T ratio, lymphocyte to target cell ratio.

Received for publication October 13, 1999. Accepted for publication December 6, 1999.

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