Lymph node and circulating T cell characteristics are strongly correlated in end‐stage renal disease patients,but highly differentiated T cells reside within the circulation

Ageing is associated with changes in the peripheral T cell immune system, which can be influenced significantly by latent cytomegalovirus (CMV) infection. To what extent changes in circulating T cell populations correlate with T cell composition of the lymph node (LN) is unclear, but is crucial for a comprehensive understanding of the T cell system. T cells from peripheral blood (PB) and LN of end‐stage renal disease patients were analysed for frequency of recent thymic emigrants using CD31 expression and T cell receptor excision circle content, relative telomere length and expression of differentiation markers. Compared with PB, LN contained relatively more CD4⁺ than CD8⁺ T cells (P < 0·001). The percentage of naive and central memory CD4⁺ and CD8⁺ T cells and thymic output parameters showed a strong linear correlation between PB and LN. Highly differentiated CD28^null T cells, being CD27^–, CD57⁺ or programmed death 1 (PD‐1⁺), were found almost exclusively in the circulation but not in LN. An age‐related decline in naive CD4⁺ and CD8⁺ T cell frequency was observed (P = 0·035 and P = 0·002, respectively) within LN, concomitant with an increase in central memory CD8⁺ T cells (P = 0·033). Latent CMV infection increased dramatically the frequency of circulating terminally differentiated T cells, but did not alter T cell composition and ageing parameters of LN significantly. Overall T cell composition and measures of thymic function in PB and LN are correlated strongly. However, highly differentiated CD28^null T cells, which may comprise a large part of circulating T cells in CMV‐seropositive individuals, are found almost exclusively within the circulation.     

Analyses of immunosenescent markers in patients with autoimmune disease

The objective of this study was to evaluate the degree of immunosenescence in patients with autoimmune disease. T cell receptor excision circles (TREC) and the percentage of CD4+CD28null T cells were studied as markers of immunosenescence in 175 patients with chronic autoimmune arthritis, other connective tissue autoimmune diseases, multiple sclerosis and 60 healthy controls. In both the rheumatoid arthritis (RA) and multiple sclerosis patient group, TREC numbers were age-inappropriately declined which points to an accelerated thymic output. Furthermore, enhanced percentages of CD4+CD28null T cells could be detected in a significant proportion of patients included in this study. These immunosenescent phenomena seemed to be present already early in the disease process. High percentages of CD4+CD28null T cells were associated with the presence of RA linked HLA DR4 alleles and with plasma reactivity to cytomegalovirus. Further analysis of CD4+CD28null T cells provided indications for a restricted T cell receptor (TCR) BV gene expression and cytoplasmic stores of various cytotoxic molecules. This study indicates that the immune system of patients with autoimmune diseases shows signs of an accelerated aging. Both genetic factors, such as HLA DR4, and environmental factors, like CMV infection, might speed up this immunosenescence and contribute in this way to disease pathogenesis.     

Premature ageing of the immune system underlies immunodeficiency in ataxia telangiectasia

ATM kinase modulates pathways implicated in premature ageing and ATM genotype predicts survival, yet immunodeficiency in ataxia telangiectasia is regarded as mild and unrelated to age. We address this paradox in a molecularly characterised sequential adult cohort with classical and mild variant ataxia telangiectasia. Immunodeficiency has the characteristics of premature ageing across multiple cellular and molecular immune parameters. This immune ageing occurs without previous CMV infection. Age predicts immunodeficiency in genetically homogeneous ataxia telangiectasia, and in comparison with controls, calendar age is exceeded by immunological age defined by thymic naïve CD4+ T cell levels. Applying ataxia telangiectasia as a model of immune ageing, pneumococcal vaccine responses, characteristically deficient in physiological ageing, are predicted by thymic naïve CD4+ T cell levels. These data suggest inherited defects of DNA repair may provide valuable insight into physiological ageing. Thymic naïve CD4+ T cells may provide a biomarker for vaccine responsiveness in elderly cohorts.     

CD8 lymphocytosis in primary cytomegalovirus (CMV) infection of allograft recipients: expansion of an uncommon CD8+ CD57- subset and its progressive replacement by CD8+ CD57+ T cells.

Allograft recipients undergoing cytomegalovirus infection present increased proportions of circulating CD8+ lymphocytes. A longitudinal study of 11 kidney and five liver allograft recipients with primary CMV infection but no other etiological factor of graft dysfunction revealed selective imbalances of peripheral blood CD8+ T cell subsets. Initially, CMV viraemia is associated with elevated CD8+bright T cell numbers and T cell activation. Activation markers fall to normal when viral cultures become negative (before the end of the first month). During the second to sixth month, most (12/16) patients keep up high CD8+ T cell counts (1050-2900 CD8+ cells/mm3), comprising an uncommon CD8+ T cell subset, as 45-73% of CD8+bright lymphocytes were CD3+ and TCR alpha beta+, but were not stained by anti-CD28, CD11b, CD16, CD56, and CD57 antibody. Unexpectedly, CD8+CD57+ T cells, a hallmark of CMV infection, do not appear until the second to sixth month of primary CMV infection, and their numbers increase progressively thereafter. They become the predominant CD8+ T cell subset after 6 months of infection and their persistence for several (up to 4) years is strongly correlated (r = 0.87) with expansion of CD8+ cells. By analysis with MoAbs, there was no bias towards the use of particular TCR-V beta gene families at any time of primary CMV infection. Persistence of CD8 lymphocytosis is thus directly related to the rate of expansion of an uncommon CD8+CD57- subset and its progressive replacement by CD8+CD57+ T cells that are chronically elicited by CMV.     

Human thymus regeneration and T cell reconstitution

The thymus supports the development of T cells throughout life from hematopoietic progenitor cells migrating from the bone marrow. During the early years after birth thymic activity is highest, but progressively declines resulting in diminished naïve T cell output. Underlying causes of thymic involution may be degeneration of the stromal thymic network, providing survival and differentiation factors for developing T cells, or insufficiency of the progenitor cells to home and/or develop in the aged thymus. In young people the reduced thymic output is insignificant, since the peripheral T cell compartment is under compensatory homeostatic control. However, in more or less immunocompromised individuals, including aged people and patients depleted of T cells due to conditioning regimens before bone marrow transplantation or HIV infection, the thymus is necessary to replenish the peripheral T cell compartment. This may require rejuvenation of the thymus. Alternatively, approaches to generate mature T cells independent of the thymus have gained considerable interest.     

Recent thymic emigrants and subsets of naive and memory T cells in the circulation of patients with head and neck cancer

Apoptosis of circulating CD8+ T lymphocytes is a frequent finding in patients with cancer. T-cell output by the thymus or antigen-driven expansion of circulating T cells could compensate for apoptosis and thus normalize their homeostasis. We studied the frequency of recent thymic emigrants (RTE) identified by T-cell receptor excision circles (TREC) and of naive and memory T-cell subsets in peripheral blood samples obtained from 39 patients with head and neck cancer (HNC) and 33 age-matched controls (NC). TREC numbers were determined by real-time quantitative PCR, and CD8+CD45RO-CD27+ or CD4+CD45RO-CD27+ T-cell subsets were quantified by flow cytometry. Age-associated decreases in TREC numbers and proportions of naive CD8+ and CD4+ T-cell subsets were significantly greater in cancer patients than NC. In contrast, the memory compartment was expanded, with increased proportions of CD4+CD45RO+ but not CD8+CD45RO+ T cells, in cancer patients vs. NC. These alterations did not normalize in patients who were NED. The data suggest that lower thymic output combined with rapid turnover of naive CD8+ T cells account for altered lymphocyte homeostasis in HNC patients. The defect persists long after curative treatments and may contribute to immune cell dysregulation in patients with cancer.     

Cytomegalovirus infection induces T-cell differentiation without impairing antigen-specific responses in Gambian infants

Cytomegalovirus (CMV) infection induces profound differentiation of T cells, and is associated with impaired responses to other immune challenges. We therefore considered whether CMV infection and the consequent T-cell differentiation in Gambian infants was associated with impaired specific responses to measles vaccination or polyclonal responses to the superantigen staphylococcal enterotoxin B (SEB). While the concentration of undifferentiated (CD27(+) CD28(+) CCR7(+)) T-cells in peripheral blood was unaffected by CMV, there was a large increase in differentiated (CD28(-) CD57(+)) CD8 T-cells and a smaller increase in differentiated CD4 cells. One week post-vaccination, the CD4 cell interferon-gamma (IFN-gamma) response to measles was lower among CMV-infected infants, but there were no other differences between the cytokine responses, or between the cytokine or proliferative responses 4 months post-vaccination. However, the CD8 T cells of CMV-infected infants proliferated more in response to SEB and the antibody response to measles correlated with the IFN-gamma response to CMV, indicating that CMV infection actually enhances some immune responses in infancy.     

Abnormal development of thymic dendritic and epithelial cells in human X-linked severe combined immunodeficiency

The X-linked form of severe combined immunodeficiency (X-SCID) is caused by mutations in the common cytokine receptor gamma chain and results in lack of T and NK cells and defective B cells. Without immune reconstitution, X-SCID patients typically die from infection during infancy. This report describes thymic epithelial (TE), lymphocyte, and dendritic cell (DC) differentiation in the thymic microenvironment of seven X-SCID patients who died before or after treatment for their immunodeficiency. X-SCID thymus consisted predominately of TE cells without grossly evident corticomedullary distinction. CD3+ and CD1a+ developing T cells and CD83+ thymic DC were reduced >50-fold when compared to age- and gender-matched control thymus (P < 0.001). TE expression of epithelial differentiation markers CK14, involucrin, and high molecular weight cytokeratins also differed in X-SCID versus normal thymus. These histopathologic findings indicate that in addition to T cells, thymic DC development and differentiation of TE cells are also abnormal in X-SCID.     

End‐stage renal disease,dialysis, kidney transplantation and their impact on CD4+ T‐cell differentiation

Premature aging of both CD4⁺ regulatory T (Treg) and CD4⁺ responder‐T (Tresp) cells in patients with end‐stage renal disease (ESRD) is expected to affect the success of later kidney transplantation. Both T‐cell populations are released from the thymus as inducible T‐cell co‐stimulator‐positive (ICOS⁺) and ICOS^? recent thymic emigrant (RTE) Treg/Tresp cells, which differ primarily in their proliferative capacities. In this study, we analysed the effect of ESRD and subsequent renal replacement therapies on the differentiation of ICOS⁺ and ICOS^? RTE Treg/Tresp cells into ICOS⁺ CD31^? or ICOS^? CD31^? memory Treg/Tresp cells and examined whether diverging pathways affected the suppressive activity of ICOS⁺ and ICOS^? Treg cells in co‐culture with autologous Tresp cells. Compared with healthy controls, we found an increased differentiation of ICOS⁺ RTE Treg/Tresp cells and ICOS^? RTE Treg cells through CD31⁺ memory Treg/Tresp cells into CD31^? memory Treg/Tresp cells in ESRD and dialysis patients. In contrast, ICOS^? RTE Tresp cells showed an increased differentiation via ICOS^? mature naive (MN) Tresp cells into CD31^? memory Tresp cells. Thereby, the ratio of ICOS⁺ Treg/ICOS⁺ Tresp cells was not changed, whereas that of ICOS^? Treg/ICOS^? Tresp cells was significantly increased. This differentiation preserved the suppressive activity of both Treg populations in ESRD and partly in dialysis patients. After transplantation, the increased differentiation of ICOS⁺ and ICOS^? RTE Tresp cells proceeded, whereas that of ICOS⁺ RTE Treg cells ceased and that of ICOS^? RTE Treg cells switched to an increased differentiation via ICOS^? MN Treg cells. Consequently, the ratios of ICOS⁺ Treg/ICOS⁺ Tresp cells and of ICOS^? Treg/ICOS^? Tresp cells decreased significantly, reducing the suppressive activity of Treg cells markedly. Our data reveal that an increased tolerance‐inducing differentiation of ICOS⁺ and ICOS^? Treg cells preserves the functional activity of Treg cells in ESRD patients, but this cannot be maintained during long‐term renal replacement therapy.     

Healthy aging and latent infection with CMV lead to distinct changes in CD8+ and CD4+ T-cell subsets in the elderly

Despite general acceptance that immunologic changes are associated with aging and latent infection with Cytomegalovirus (CMV), no clear-cut distinction has so far been made between strictly age-related and CMV-induced changes. We therefore compared CD4+ and CD8+ na?ve (CD45RA+CD28+), memory (CD45RA-CD28+), and effector (CD28-) T cells in CMV-positive (n = 164) and CMV-negative (n = 87) elderly persons and correlated CD8+ and CD4+ effector T cells with other T-cell subpopulations. Percentages of CD8+ as well as CD4+ effector T cells were higher, but percentages of na?ve and memory cells were lower in CMV-positive compared to CMV-negative elderly persons. Negative correlations within CD8+ T-cell subsets were found to be present in both CMV-positive and CMV-negative elderly individuals. In contrast, correlations within CD4+ T-cell subpopulations and a positive correlation between CD8+ and CD4+ effector T cells were found in CMV-positive individuals only. Our results demonstrate that (a) in the elderly different T-cell subsets compete for space within the CD8+, but not the CD4+ T-cell population; (b) CMV induces changes in the CD4+ compartment that differ from the solely age-related changes seen in CMV-negative elderly population; and (c) the CMV-status of a population has to be taken into account before a conclusion on the effect of aging on the composition of the T-cell pool can be reached.     

Assessment of thymic output in common variable immunodeficiency patients by evaluation of T cell receptor excision circles

Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by repeated infections and hypogammaglobulinaemia. Additionally, T-cell abnormalities including lymphopenia, decreased proliferation to mitogens and antigens, and the reduced production and expression of cytokines, have also been observed. In this study we have investigated the expression of naive, memory and activation markers in T-cell subpopulations in 17 CVID patients in comparison to age-matched normal controls. The numbers of CD4+ T cells, including CD45RA+CD62L+ and, to a lesser extent, CD45RA-CD62L+/RA+CD62L- were significantly reduced in patients, whereas CD8+ T cells were within normal range. In contrast, HLA-DR+ cells were increased both in CD4+ and CD8+ T cells. To assess the thymic output, we analysed the presence of T-cell receptor excision circles (TRECs) in CD4+ and CD8+ T cells by quantitative PCR. TRECs were decreased significantly in patients and the rate of TREC loss was higher with increasing age. TRECs correlated with naive CD4+ T cells, whereas there was an inverse relationship between TRECs and CD8+HLA-DR+ and CD8+CD45RA-CD62L+/RA+CD62L- T cells. Our results suggest the presence of a defect in the naive T cell compartment with origin at the thymic level in CVID, and indicate that TREC may be a useful marker to monitor thymic function in this primary immunodeficiency.     

Rapid T cell repopulation after rabbit anti-thymocyte globulin (rATG) treatment is driven mainly by cytomegalovirus

Rabbit anti-thymocyte globulin (rATG) induces a long-lasting lymphocytopenia. CD4(+) T cells remain depleted for up to 2 years, whereas the CD8(+) T cell compartment is refilled rapidly by highly differentiated CD27(-) CD45RA(+) CD57(+) effector-type cells. Because the presence of these highly differentiated CD8(+) T cells has been associated with cytomegalovirus (CMV) infection, we questioned to what extent restoration of CMV T cell immunity contributes to the re-emergence of T cells following rATG treatment. We compared T cell repopulation in six CMV-seropositive patients with CMV reactivation (reactivating CMV(+) ) to that in three CMV(+) patients without reactivation (non-reactivating CMV(+) ), and to that in three CMV-seronegative recipients receiving a kidney from a CMV-seronegative donor (CMV(-/-) ). All patients received rATG because of acute allograft rejection. Total CD4 and CD8 counts, frequency and phenotype of virus-specific CD8(+) T cells were determined. In reactivating CMV(+) patients, total CD8(+) T cells reappeared rapidly, whereas in non-reactivating CMV(+) patients they lagged behind. In CMV(-/-) patients, CD8(+) T cell counts had not yet reached pretransplant levels after 2 years. CMV reactivation was indeed followed by a progressive accumulation of CMV-specific CD8(+) T cells. During lymphocytopenia following rATG treatment, serum interleukin (IL)-7 levels were elevated. Although this was most prominent in the CMV-seronegative patients, it did not result in an advantage in T cell repopulation in these patients. Repopulated CD8(+) T cells showed increased skewing in their Vβ repertoire in both CMV(-/-) and reactivating CMV-seropositive patients. We conclude that rapid T cell repopulation following rATG treatment is driven mainly by CMV.     

Adoptive transfer of cytomegalovirus‐specific effector CD4+ T cells provides antiviral protection from murine CMV infection

Cytomegalovirus (CMV) infects a majority of the human population and establishes a life‐long persistence. CMV infection is usually asymptomatic but the virus carries pathogenic potential and causes severe disease in immunocompromised individuals. T‐cell‐mediated immunity plays an essential role in control of CMV infection and adoptive transfer of CMV‐specific CD8⁺ T cells restores viral immunity in immunosuppressed patients but a role for CD4⁺ T cells remains elusive. Here, we analyzed in adoptive transfer studies the features and antiviral functions of virus‐specific CD4⁺ T cells during primary murine CMV (MCMV) infection. MCMV‐specific CD4⁺ T cells expanded upon MCMV infection and displayed an effector phenotype and function. Adoptive transfer of in vivo activated MCMV‐specific CD4⁺ T cells to immune‐compromised mice was protective during pathogenic MCMV infection and IFN‐γ was a crucial mediator of this protective capacity. Moreover, co‐transfer of low doses of both MCMV‐specific CD4⁺ T cells and CD8⁺ T cells synergized in control of lytic viral replication in immune‐compromised mice. Our data reveal a pivotal antiviral role for virus‐specific CD4⁺ T cells in protection from pathogenic CMV infection and provide evidence for their antiviral therapeutic potential.     

Mouse thymic virus-mediated immunosuppression: association with decreased helper T cells and increased suppressor T cells

Mouse thymic virus (MTV) is a herpesvirus which, when administered to newborn mice, induces an extensive but temporary thymic necrosis associated with immunosuppression. In the present study, the T cell subsets in the thymus of MTV infected newborn C57Bl/6 mice were evaluated at 4, 7, 14, 28, 56, and 84 days after infection, using labeled monoclonal anti-CD4 and anti-CD8 antibodies with two-color flow cytometry. At 7 and 14 days, the percentages of CD4+8- and CD4+8+ cells were significantly decreased whereas the percentage of CD4-8+ cell was increased. At days 28 and 56 percentages had returned to normal. These results indicate that the virus has an affinity for CD4+ T cells (helper cells and their precursors). Increased percentage of CD4-8+ T cells (suppressor cells) is also associated with depressed immune functions in MTV infected newborn mice.     

CMV drives the expansion of highly functional memory T cells expressing NK‐cell receptors in renal transplant recipients

Cytomegalovirus (CMV) is a common opportunistic infection encountered in renal transplant recipients (RTRs) and may be reactivated without symptoms at any time post‐transplant. We describe how active and latent CMV affect T‐cell subsets in RTRs who are stable on maintenance therapy. T‐cell responses to CMV were assessed in RTRs (n = 54) >2 years post‐transplant, and healthy controls (n = 38). Seven RTRs had CMV DNA detectable in plasma. CMV antibody and DNA aligned with increased proportions of CD8⁺ T cells and reduced CD4/CD8 ratios. This paralleled an expansion of effector memory T‐cell (T_EM), terminally differentiated T‐cell (T_EMRA) and CD57⁺ T_EMRA cell populations. Expression of NK‐cell receptors, LIR‐1 and KLRG1 on CD4⁺ and CD8⁺ CD57⁺ T_EM and T_EMRA cells correlated with elevated interferon‐γ and cytotoxic responses to anti‐CD3 and increased cytotoxic responses to CMV phosphoprotein (pp) 65 in RTRs who carried CMV DNA. CD8⁺ T cells from all CMV seropositive RTRs responded efficiently to CMV immediate early (IE) ‐1 peptides. The data show that latent and active CMV infection can alter T‐cell subsets in RTRs many years after transplantation, and up‐regulate T‐cell expression of NK‐cell receptors. This may enhance effector responses of CD4⁺ and CD8⁺ T cells against CMV.     

CD27 and CD57 expression reveals atypical differentiation of human immunodeficiency virus type 1-specific memory CD8+ T cells

The failure of human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T cells to control chronic HIV-1 infection could be due to the progressive loss of their capacities to undergo normal memory effector differentiation. We characterized and compared the expressions of CD27, CD28, CD57, and CD62L by Epstein-Barr virus (EBV)-, cytomegalovirus (CMV)-, and HIV-1-specific CD8+ T cells by six-color, eight-parameter flow cytometry. In contrast to the maturation of EBV- and CMV-specific memory CD8+ T cells, we found that HIV-1-specific CD8+ T cells did not display coordinated down-regulation of CD27 and up-regulation of CD57 and accumulated in an atypical CD27(high) CD57(low) subset. Moreover, the accumulation of CD27(high) CD57(low) HIV-1-specific CD8+ T cells was positively correlated with HIV-1 plasma viremia. The differentiation of HIV-1-specific CD8+ T cells to an effector subset is therefore impaired during chronic HIV-1 infection. This lack of normal CD8+ T-cell differentiation could contribute to the failure of cellular immune control of HIV-1 infection.     

Kv1.3 channels as a potential target for immunomodulation of CD4+ CD28null T cells in patients with acute coronary syndrome

Modulation of CD4(+)CD28null T cells through K+ channels could provide potential novel targets for the treatment acute coronary syndrome (ACS). However, the surface phenotype and K+ channel expression of CD4(+)CD28null T cells in patients with ACS is unclear. The aim of this study was to investigate the surface phenotype and K+ channel expression of CD4(+)CD28null T cells in patients with ACS. We found that more than 80% of CD4(+)CD28null T cells in patients with ACS showed a CD45RA(-)CD45RO(+)CCR7- surface phenotype. CD4(+)CD28(null) T expressed small numbers of the voltage-gated Kv1.3 and intermediate-conductance Ca2+-activated K+ channel KCa3.1 when quiescent, but increased Kv1.3 expression 4-fold with little change in KCa3.1 levels upon activation. Consistent with their channel phenotypes, the production of interferon-γ and perforin in CD4(+)CD28null T cells was suppressed by the specific Kv1.3 blocker 5-(4-phenoxybutoxy)psoralen PAP-1. Therefore, selective targeting of Kv1.3 in CD4(+)CD28null T cells may hold potential therapeutic promise for ACS.     

Maturational alterations of peripheral T cell subsets and cytokine gene expression in 22q11.2 deletion syndrome

Chromosome 22q11.2 deletion syndrome is a common disorder characterized by thymic hypoplasia, conotruncal cardiac defect and hypoparathyroidism. Patients have a risk of infections and autoimmunity associated with T lymphocytopenia. To assess the immunological constitution of patients, the numerical changes and cytokine profile of circulating T cells were analysed by flow cytometry and real-time polymerase chain reaction (PCR). CD3+, CD4+, T cell receptor (TCR)alphabeta+ or CD8alphaalpha+ cell counts were lower, and CD56+ cell counts were higher in patients than in controls during the period from birth to adulthood. The ageing decline of CD3+ or CD4+ cell counts was slower in patients than in controls. The proportion of CD8alphaalpha+ cells increased in controls, and the slope index was larger than in patients. On the other hand, both the number and proportion of Valpha24+ cells increased in patients, and the slope indexes tended to be larger than in controls. The positive correlation of the number of T cells with CD8alphaalpha+ cells was observed only in patients, and that with Valpha24+ cells was seen only in controls. No gene expression levels of interferon (IFN)-gamma, interleukin (IL)-10, transforming growth factor (TGF)-beta, cytotoxic T lymphocyte antigen 4 (CTLA4) or forkhead box p3 (Foxp3) in T cells differed between patients and controls. There was no significant association between the lymphocyte subsets or gene expression levels and clinical phenotype including the types of cardiac disease, hypocalcaemia and frequency of infection. These results indicated that T-lymphocytopenia in 22q11.2 deletion patients became less severe with age under the altered composition of minor subsets. The balanced cytokine profile in the limited T cell pool may represent a T cell homeostasis in thymic deficiency syndrome.     

CD28 controls the development of innate‐like CD8+ T cells by promoting the functional maturation of NKT cells

NK T cells(NKT cells) share functional characteristics and homing properties that are distinct from conventional T cells. In this study, we investigated the contribution of CD28 in the functional development of γδ NKT and αβ NKT cells in mice. We show that CD28 promotes the thymic maturation of promyelocytic leukemia zinc finger⁺ IL‐4⁺ NKT cells and upregulation of LFA‐1 expression on NKT cells. We demonstrate that the developmental defect of γδ NKT cells in CD28‐deficient mice is cell autonomous. Moreover, we show in both wild‐type C57BL/6 mice and in downstream of tyrosine kinase‐1 transgenic mice, a mouse model with increased numbers of γδ NKT cells, that CD28‐mediated regulation of thymic IL‐4⁺ NKT cells promotes the differentiation of eomesodermin⁺ CD44^high innate‐like CD8⁺ T cells. These findings reveal a previously unappreciated mechanism by which CD28 controls NKT‐cell homeostasis and the size of the innate‐like CD8⁺ T‐cell pool.     

Limited role for the thymus in SIV pathogenesis

The role of the thymus in the pathogenesis of AIDS is a frequently discussed and controversial topic. Tuttleton Arron et al. studied the role of thymic output in SIV infection directly, by comparing the dynamics of TCR excision circles and CD4(+ )and CD8(+) T cell numbers in healthy and in SIV-infected euthymic and thymectomized rhesus macaques. In this issue of the European Journal of Immunology, they report that complete abrogation of thymic output in juvenile rhesus macaques has very little impact on the peripheral T cell compartment, both in healthy and in SIV-infected macaques. Their data therefore suggest that the main cause of CD4(+) T cell loss during SIV infection is the peripheral effect of SIV, and not its effect on thymic output.