Ageing combines CD4 T cell lymphopenia in secondary lymphoid organs and T cell accumulation in gut associated lymphoid tissue
© Martinet et al.; licensee BioMed Central Ltd. 2014
Received: 21 October 2013
Accepted: 29 April 2014
Published: 8 May 2014
CD4 T cell lymphopenia is an important T cell defect associated to ageing. Higher susceptibility to infections, cancer, or autoimmune pathologies described in aged individuals is thought to partly rely on T cell lymphopenia. We hypothesize that such diverse effects may reflect anatomical heterogeneity of age related T cell lymphopenia. Indeed, no data are currently available on the impact of ageing on T cell pool recovered from gut associated lymphoid tissue (GALT), a crucial site of CD4 T cell accumulation.
Primary, secondary and tertiary lymphoid organs of C57BL/6 animals were analysed at three intervals of ages: 2 to 6 months (young), 10 to 14 months (middle-aged) and 22 to 26 months (old). We confirmed that ageing preferentially impacted CD4 T cell compartment in secondary lymphoid organs. Importantly, a different picture emerged from gut associated mucosal sites: during ageing, CD4 T cell accumulation was progressively developing in colon and small intestine lamina propria and Peyer’s patches. Similar trend was also observed in middle-aged SJL/B6 F1 mice. Interestingly, an inverse correlation was detected between CD4 T cell numbers in secondary lymphoid organs and colonic lamina propria of C57BL/6 mice whereas no increase in proliferation rate of GALT CD4 T cells was detected. In contrast to GALT, no CD4 T cell accumulation was detected in lungs and liver in middle-aged animals. Finally, the concomitant accumulation of CD4 T cell in GALT and depletion in secondary lymphoid organs during ageing was detected both in male and female animals.
Our data thus demonstrate that T cell lymphopenia in secondary lymphoid organs currently associated to ageing is not sustained in gut or lung mucosa associated lymphoid tissues or non-lymphoid sites such as the liver. The inverse correlation between CD4 T cell numbers in secondary lymphoid organs and colonic lamina propria and the absence of overt proliferation in GALT suggest that marked CD4 T cell decay in secondary lymphoid organs during ageing reflect redistribution of CD4 T cells rather than generalized CD4 T cell decay. Such anatomical heterogeneity may provide an important rationale for the diversity of immune defects observed during ageing.
Increased susceptibility to infections, cancer [1, 2] or some auto-immune pathologies [3, 4] are immune defects commonly associated to ageing . The impact of ageing on T cell compartment is commonly defined by reduction of thymic production, T cell lymphopenia, increased of effector/memory T cells subsets [6, 7]. Additionally, intrinsic defects affecting T cell responsiveness have been described : altered cell membrane fluidity , alteration of cell surface expression of co-stimulatory molecules and cytokine receptors, molecular and transcriptional changes . T cell lymphopenia, i.e. decrease in T cell number, has been extensively described during human [11–13] and mice ageing [14, 15] and is considered as an important cofactor of age related immune defects. However, the mechanisms by which T cell lymphopenia contribute both to defective and/or exacerbated immune responses in context of infection or autoimmunity respectively remain uncertain. Two opposing immune alterations have been essentially associated to T cell lymphopenia so far. A first mechanism is the loss of clonal diversity [16–20] presumably leading to the inability of elderly to respond to certain pathogens. It is commonly related to progressive decrease in thymic export [21–23] although such mechanism is probably not exclusive [24–27]. Importantly, loss of diversity is not consistently described in human analyses and remains to be fully characterized . The second alteration commonly related to age is the higher proportion of effector/memory cells among conventional T cells in aged individuals . The age related skewing of naïve T cells towards effector and/or memory T cells is thought to reflect both loss of naïve T cell production and lymphopenia induced proliferation (LIP) of naïve T cells [30, 31]. It has been claimed that such exacerbated immune responses may lead to auto-immune pathologies [3, 4]. However, LIP essentially occurred in context of severe lymphopenia (such as constitutively lymphopenic hosts) and may not develop in context of partial lymphopenia such as observed in ageing [14, 32]. Thus, the exact relationship between diversity of age-related immune defects and T cell lymphopenia remains under debate. We hypothesize that age-related T cell lymphopenia develops differently in secondary lymphoid organs compared to tertiary lymphoid organs and non-lymphoid tissues. Indeed, T cell lymphopenia has been essentially described in secondary lymphoid organs and blood. However, very little information is currently available on T cell compartment in mucosa associated lymphoid tissues (MALT) such as gut or lung associated lymphoid tissue or non-lymphoid tissues. We focused on gut associated lymphoid tissue (GALT) that is presumably highly relevant to CD4 T cell homeostasis  and readdressed T cell lymphopenia during ageing by performing an exhaustive analysis of the impact of ageing on T cell compartment integrating anatomical location. We analysed CD4 and CD8 T cell compartments in secondary (i.e. mesenteric lymph nodes, superficial lymph nodes, and spleen either globally or separately), tertiary lymphoid organs (as MALT) and non-lymphoid tissue (liver) for different ages ranges (young (2–6 months old), middle-aged (10–14 months old) and old C57BL/6 animals (22–26 months old)).
We confirmed that ageing preferentially affected CD4 T cell compartment in secondary lymphoid organs. We demonstrated that ageing induces concomitantly CD4 T cell decay in secondary lymphoid organs (and notably superficial lymph nodes) and increase of CD4 T cell numbers in the lamina propria of colon and small intestine and Peyer’s patches. Such aged related CD4 T cell accumulation was locally restricted since liver or lungs did not show any difference with age in CD4 T cell absolute numbers. Interestingly, an inverse association was detected between CD4 T cell numbers recovered in secondary lymphoid organs and in colonic lamina propria. Secondly, we demonstrated that T cell accumulation in GALT was not related to higher proliferation of GALT CD4 T cells during ageing. Collectively these data suggest that CD4 T cell lymphopenia commonly described in secondary lymphoid organs (and blood) during ageing may reflect altered redistribution of CD4 T cells rather than extensive depletion. Such anatomical heterogeneity may provide an important rationale for the diversity of immune defects observed during ageing and lead to drastically re-evaluate the notion of age related T cell lymphopenia.
Differential CD4 and CD8 decay in lymphoid organs depending on age
Collectively, analysing naïve and effector/memory absolute numbers provided interesting insights on the shift of naïve T cells towards effector/memory T cells during ageing. We observed that physiological ageing is not equally affecting CD4 and CD8 T cell pools. Total CD4 T cell decay reflected massive reduction of naïve CD4 T cells occurring in middle-aged animals combined to a mild increase of effector/memory CD4 T cells in old animals. A different timeline emerged when considering CD8 T cell compartment: naïve and effector/memory CD8 T cells numbers were essentially not affected in middle-aged animals in contrast to older animals who exhibited clear naïve CD8 T cell decay and increase in effector/memory CD8 T cells.
T cell decay differed depending on the second lymphoid organs considered
Age associated T cell accumulation in gut associated lymphoid tissue during ageing
Association between CD4 T cell lymphopenia in secondary lymphoid organs and accumulation in gut associated lymphoid tissue
Simultaneous accumulation of CD4 T cell at mucosal sites and the development of T cell lymphopenia at lymphoid sites raised the question of a direct association between these two phenomena during ageing. Indeed, a strong inverse association was observed between CD4 T cell numbers in colonic lamina propria (cLP) sites and lymphoid sites (Figure 4C). To note, the association was not detected when considering small intestine lamina propria (siLP) or Peyer’s patches (PP) presumably due to the limited variation in numbers observed in these organs. Indeed, ageing induced a 6-fold increase in CD4 T cells in cLP but a 2-fold increase in siLP and PP.
Collectively, our data suggest that CD4 T cell increase observed in the GALT reflect progressive recruitment and accumulation of CD4 T cells from lymphoid sites rather than peripheral expansion of gut resident CD4 T cells.
Age dependent CD4 T cell accumulation in gut associated lymphoid tissue but not in lungs or liver
No major influence of sex on CD4 T cell distribution during ageing
Sex of animals and sex hormones may differentially regulate CD4 homeostasis . To ascertain whether CD4 T cell redistribution in cLP occurs equally in male and female animals, we analysed CD4 T cell distribution based on the sex of the animals. As shown in Figure 6B, sex had only minor influence on CD4 T cell lymphopenia at lymphoid sites and CD4 T cell accumulation at mucosal sites. Comparing young, intermediate and old animals, we observed an equal decay of thymocytes in male and female animals. In pooled secondary lymphoid organs, CD4 T cells decay was observed in both groups, although significantly more exacerbated in female animals (p 0.0156 when comparing old groups). Conversely, CD4 T cell numbers recovered in cLP were equally increased in male and female animals. These data demonstrate that CD4 T cell accumulation in gut associated lymphoid tissue associated to CD4 T cell lymphopenia during ageing occurs both in male and female animals, although the amplitude of CD4 T cell depletion in lymphoid organs appeared to be more drastic among female mice.
Ageing is a multifactorial process [24, 25] integrating general metabolic changes and immune specific alterations such as progressive decrease in thymic export [21–23]. An expected consequence of declining T cell production is the development of progressive T cell lymphopenia. The incidence of T cell lymphopenia during human ageing is extensively reported in blood samples [11–13] but a more controversial picture emerges from lymphoid organs in murine studies. T cell numbers recovered from spleen or pooled secondary lymphoid organs are reported to be unchanged [24, 39] or reduced [14, 15] depending notably on the organs considered. In that respect, our current analysis in C57BL/6 mice reconciles this apparent contradiction regarding cell numbers recovered from secondary lymphoid organs: mesenteric lymph nodes and spleen being essentially preserved, whereas superficial lymph nodes studied exhibited significant T cell depletion affecting primarily CD4 T cell in middle-aged animals but also CD8 T cells at older ages. A second common observation regarding immune ageing is the differential behaviour of CD4 and CD8 T cell compartments when ageing developed . Evidence of T cell lymphopenia differently affecting CD4 and CD8 T cell compartments is also described in bone marrow transplantation protocols or in a model of genetic thymectomy [15, 34, 35]. These differential behaviours of CD4 and CD8 T cells are also substantiated by phenotypic and molecular analyses [28, 36, 44]. Numerous publications attribute such differential behaviour to specific age related oligoclonal expansion of CD8 T cells both in mice and humans [45–48]. Accordingly, we observed that CD4 T cell numbers recovered from secondary lymphoid organs were rapidly affected: a significant decay was detected in middle-aged animals, whereas CD8 T cells were essentially preserved. However, we demonstrated here that differential behaviour of CD4 and CD8 T cells also arise among their naïve T cell compartments. The size of the naïve T cell compartment theoretically results from the combined effect of thymic production, homeostatic control and peripheral activation leading to recruitment of T cells from the naïve pool. Because loss of thymic production observed during ageing affects equally single positive CD4 or CD8 thymocytes production , our results suggest that naïve CD8 T cells are preserved due to poor turn over, whereas naïve CD4 T cell pool appears highly stimulated and directly impacted by partial reduction in thymic production. This faster consumption rate of CD4 T cells may reflect the more pleiotropic function of CD4 T cells compared to CD8 T cells, CD4 T cells being central partners of innate, humoral and cytotoxic responses.
A third classical feature of T cell ageing is a shift from naïve towards effector/memory T cell predominance observed in blood and lymphoid organs . This shift may rely on either naïve T cell decay and/or increase of the effector/memory fraction. By providing naïve and effector/memory absolute numbers, we demonstrated that a different balance between naïve decay and increase in effector/memory cells seems to develop among CD4 and CD8 T cells. In middle-aged animals, naïve CD4 T cell decay was prominent whereas effector/memory CD4 T cell numbers were, albeit significantly, only mildly increased. To note, we excluded regulatory T cells, a particular subset of CD4 T cells exhibiting suppressive activity, from naïve and effector/memory CD4 T cell pool analysis. In contrast, CD8 T cell numbers were essentially preserved in middle-aged animals: no significant difference was detected when considering total, naïve or effector/memory CD8 T cell numbers separately. In old animals, a different picture emerged: a prominent increase in effector/memory CD8 but not CD4 T cells was detected. Our data suggest that changes in activation profile is essentially related to decrease in naïve T cell numbers when considering CD4 T cell compartment, whereas oligoclonal CD8 expansion occurring in older mice also contributes to naïve towards effector/memory shift among CD8 T cell compartment. Collectively, we demonstrated the existence of an unparalleled impact of ageing on naïve CD4 and effector/memory CD8 T cells.
More importantly, we provided in this report the first evaluation of the impact of ageing on CD4 and CD8 T cells residing in secondary and tertiary lymphoid organs and in non-lymphoid tissues. In striking contrast to secondary lymphoid organs, we detected a progressive accumulation of CD4 T cells in all gut associated lymphoid tissues (GALT) considered: Peyer’s patches, lamina propria from the small intestine and the colon. Such increase was not detected for CD8 T cells in Peyer’s patches but was observed at a lesser amplitude in lamina propria. CD4 T cell numbers recovered from lamina propria were consistently up to 6-fold higher than CD8 T cell numbers recovered. Thus, although both CD4 and CD8 T cells appear to accumulate in the lamina propria with age, such effect may be particularly crucial for the CD4 T cell compartment. As a control, we next analysed CD4 and CD8 T cell accumulation in lungs and liver. CD8 but not CD4 T cell accumulation was detected in the lungs mucosa associated lymphoid tissues suggesting CD4 T cell accumulation in the intestine was a specific feature of the GALT. Analyses of T cell recovery in the liver revealed essentially preserved T cell numbers although later time points may be required to fully ascertain the impact of ageing on liver resident T cells. This observation is in accordance with previous publications demonstrating a high increase of DN T cell rather than CD4 or CD8 T cells in aged liver [40, 41]. Thus, CD4 and CD8 T cell distribution/accumulation during ageing appears highly differing depending on the tissues considered. The mechanisms responsible for such predominant age dependent accumulation of CD4 T cells in the GALT remain to be further investigated. Two main hypotheses can be formulated: CD4 T cell accumulation in the intestine may reflect age related skewing of CD4 T cell distribution from secondary lymphoid organs to the GALT or specific proliferative activity of CD4 T cells residing in the gut ensuring local CD4 T cell production. Evaluating Ki67 expression in GALT CD4 T cells provided insight showing that local proliferation is not significantly increased but even reduced during ageing. This observation suggests that change in T cell numbers in the gut are predominantly induced by recruitment rather than local proliferation. Accordingly, preserved proportion of FOXP3+ regulatory T cells suggests that CD4 T cell accumulation applies to both conventional and regulatory T cells. Additionally, we detected an association between the severity of T cell lymphopenia at lymphoid sites and CD4 T cell accumulation in colonic lamina propria (cLP). The absence of association with small intestine lamina propria (siLP) may reflect either the lower fold of CD4 T cell accumulation in siLP although different mechanisms of accumulation developing in cLP and siLP respectively cannot be excluded. Increasing numbers of reports demonstrated the crucial role of microbial colonization of mucosal site and mucosal immunity on immune responses [50, 51]. It is tempting to speculate that mucosal immunity may directly influence the severity of lymphoid T cell lymphopenia. However, we cannot strictly discriminate in our experimental settings the causal or consequential link between lymphoid T cell lymphopenia and mucosal accumulation. This question will require further investigations.
Collectively, analyses of T cell recovery in multiple sites indicate that T cell lymphopenia is not a consistent feature of ageing: T cell lymphopenia was essentially restricted to the CD4 subset in some secondary lymphoid organs. Such heterogeneity questions the exact incidence of T cell lymphopenia developing during ageing. One may consider that redistribution of CD4 T cells rather than T cell lymphopenia is the crucial phenomena occurring during ageing.
Finally, these observations are also highly relevant in context of accelerated ageing. For instance, HIV infection is frequently defined as accelerated ageing, due to persistent T cell lymphopenia and skewed naïve to effector/memory phenotype. However, HIV infection is associated to drastic CD4 T cell depletion in the gut prior to the progressive depletion detected in the blood . Such observation constitutes a major drawback to the characterization of HIV infection as an accelerated ageing process. One may question the long-term thread that local CD4 T cell depletion in the gut may induce in old HIV infected patients.
Our results demonstrate that T cell lymphopenia commonly associated to secondary lymphoid organs is surprisingly restricted to these specific sites, and is not applicable to important sites of T cell accumulation such as gut associated lymphoid tissue (GALT). These results are in accordance with a high degree of compartmentalization among organs previously described [53, 54]. Ageing appears to induce tissue-specific modulation of T cell compartments: ageing was associated with significant increase in CD8 T cells in lungs, mixed CD4 and CD8 T cell accumulation in GALT, and no change in the liver. Marked decay of CD4 T cells in secondary lymphoid organs during ageing may rely on different sites of CD4 T cell accumulation rather than generalized CD4 T cell decay. Such observation refreshes the concept of age related T cell lymphopenia by favouring a model of age related change in T cell distribution among secondary, tertiary and non-lymphoid sites. The concept of tissular heterogeneity of ageing may also provide an interesting rationale for the diverse effects of ageing on immune responses.
6 to 8 weeks old C57BL/6 mice were purchased from Janvier Laboratories, and mated in our facilities. Mice were sacrificed at 2 to 6 months of age, 10 to 14 months of age and at 22 to 26 months old respectively named “young”, “middle-aged” and “old” animals. Mice were maintained under pathogen free conditions at the central animal facility of Paris-Sud Faculty of Medicine. As control, young (2 months, n = 6) and middle aged B6-SJL F1 animals (11 months, n = 6) were also analysed. All protocols were conducted in compliance with French and European animal welfare regulations (agreement B-94-043-12 and license 94–440, delivered by the French veterinary authorities) and validated by the Ethics Committee of University Paris-Sud (CEEA27).
Lymphoid organs cell purification
Single cell suspensions were prepared from lymph nodes (mesenteric and pooled inguinal, brachial, axillary), spleens, thymus and Peyer’s Patches in DMEM High Glucose containing 10% FCS and 20 mM Hepes buffer (PAA Laboratories GmbH) by dilaceration on 70-μm-mesh cell strainer (BD biosciences).
Cell isolation from small intestine and colon lamina propria
Intestines were treated following standard procedures . Intestines were washed with PBS 1X, mesentery and fat were removed. Peyer’s patches from small intestine were excised and treated as described above. Intestines were then opened longitudinally, cut into 1 cm pieces, and washed 5 times for 10 min at 37°C in pre-warmed PBS 1X containing 3 mM EDTA. Intestine pieces were then washed for 10 min at 37°C in pre-warmed PBS 1X. The tissues were digested in collagenase 100 U/mL (Sigma) and DNase 50 U/mL (Sigma) in pre-warmed RPMI 1640 containing 10% FBS and 20 mM Hepes buffer at 37°C for 45 min. Aspirating 10–15 times the suspension using a 10 mL syringe completed the digestion. All incubations were done under magnetically agitation. Cell suspensions were washed twice in DMEM High Glucose containing 10% FCS and 20 mM Hepes buffer before flow cytometry staining.
Lymphocyte isolation from liver and lungs
Liver single cell suspensions were collected in DMEM High Glucose containing 10% FCS and 20 mM Hepes buffer (PAA Laboratories GmbH), following dilaceration on 100 μm mesh cell strainer. Lungs were washed with PBS 1X, finely minced and stirred in PBS 1X with 400 μg/mL Liberase (Roche) during 20 minutes at 37°C under 250 rpm agitation; suspensions were subsequently filtered and dilacerated on 70 μm mesh cell strainer. Finally, Ficoll centrifugation at 2500 rpm was performed for 20 minutes to isolate lymphocytes. These lymphocyte suspensions were washed twice in DMEM High Glucose containing 10% FCS and 20 mM Hepes buffer before flow cytometry staining.
Absolute numbers determination
Cells counts were performed in duplicates after addition of Trypan blue dye using Malassez haemocytometer cell.
Extracellular staining was preceded by incubation with purified anti-CD16/32 antibodies (FcγRII/III block, 2.4G2) (eBioscience) to block non-specific staining. Cells were stained with FITC-, PE-, PerCP-Cy5.5-, PE-Cy5-, PE-Cy7-, APC-, and APC-H7- labelled appropriate antibodies including: TCRβ (H57-597, eBioscience); CD45 (30-F11, eBioscience and BD Biosciences); CD44 (IM7, eBioscience); CD8α (53–6.7, eBioscience); CD62L (MEL-14, eBioscience); CD4 (GK1.5, BD Biosciences and Miltenyi Biotec); or appropriate isotype Abs. Intranuclear FOXP3 staining was performed using eBioscience PE- or APC-conjugated FOXP3 staining buffer set (FJK-16 s). Intranuclear Ki-67 staining was performed using BD Pharmingen Ki-67 (B56) on permeabilized cells. Six-colour flow cytometry was performed with a FACSCanto cytometer (BD Biosciences). Data files were analysed using FlowJo software (Tree star Inc.).
Statistical analyses were performed using unpaired Student’s t test with Graph Pad Software. Mean and standard error mean of experiments are shown. Association were tested using a Spearman test.
This work was supported by the ANRS (Agence Nationale de la Recherche contre le SIDA et les hépatites C), la Fondation pour la Recherche Médicale (FRM) and benefited from donations of the CIC bank (Crédit Industriel et Commercial) and Pericles consulting group. We thank Elisabeth Huc and Laurent Potier who kindly provided SJL/B6 F1 mice. We thank Dr C. Tanchot and Dr F. Simonetta for critical reading, and Prs M. Tardieu and J.F. Delfraissy for their support.
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