Mel14+CD4+ T cells from aged mice display functional and phenotypic characteristics of memory cells

CD4+ T cell responses are associated with disease control in chronic viral infections. We analyzed human immunodeficiency virus (HIV)-specific responses in ten aviremic and eight viremic patients treated during primary HIV-1 infection and for up to 6 yr thereafter. Using a highly sensitive 5-(and-6)-carboxyfluorescein diacetate-succinimidyl ester–based proliferation assay, we observed that proliferative Gag and Nef peptide-specific CD4+ T cell responses were 30-fold higher in the aviremic patients. Two subsets of HIV-specific memory CD4+ T cells were identified in aviremic patients, CD45RA− CCR7+ central memory cells (Tcm) producing exclusively interleukin (IL)-2, and CD45RA− CCR7− effector memory cells (Tem) that produced both IL-2 and interferon (IFN)-γ. In contrast, in viremic, therapy-failing patients, we found significant frequencies of Tem that unexpectedly produced exclusively IFN-γ. Longitudinal analysis of HIV epitope–specific CD4+ T cells revealed that only cells that had the capacity to produce IL-2 persisted as long-term memory cells. In viremic patients the presence of IFN-γ–producing cells was restricted to periods of elevated viremia. These findings suggest that long-term CD4+ T cell memory depends on IL-2–producing CD4+ T cells and that IFN-γ only–producing cells are short lived. Our data favor a model whereby competent HIV-specific Tcm continuously arise in small numbers but under persistent antigenemia are rapidly induced to differentiate into IFN-γ only–producing cells that lack self-renewal capacity.

Download Full-text

The Role of IL-12 and IL-23 in the Generation and Maintenance of Memory CD4+ T Cells.

Blood ◽

10.1182/blood.v104.11.2664.2664 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2664-2664

Author(s):

Aileen M. Cleary ◽

David B. Lewis

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Chemokine Receptors ◽

Human Memory ◽

Surface Expression ◽

Effector Memory ◽

Memory Cells ◽

Peripheral Lymph ◽

And Function ◽

Memory Cd4 T Cells

Abstract Human memory CD4+ T cells can be distinguished from antigenically-naïve CD4+ T cells based on their CD45RAlowCD45R0high and CD45RAhighCD45R0low surface phenotypes, respectively. Memory CD4+ T cells from adult peripheral blood can be further divided based on surface expression of the CCR7 chemokine receptor. Th1 memory CD4+ T cells that are CCR7high (putative central memory cells or Tcm) are expected to be preferentially targeted to peripheral lymph nodes where the ligands for CCR7 are expressed in high amounts. These cells have been reported to lack expression of the CCR3 and CCR5 chemokine receptors, which facilitate entry into inflamed tissues, and produce little or no interferon (IFN)-γ after stimulation via the αβ-TCR/CD3 complex. CD45RAlowCD45R0highCCR7low CD4+ T cells account for virtually all IFN-g production by human CD4 T cells after ab-TCR/CD3 stimulation using monoclonal antibodies, and for this reason were termed effector memory cells (Tem). These findings, as well as the observation of shorter telomere lengths for memory CD4+ T cells that are CCR7low compared to those that CCR7high suggest that the Tcm population may be an intermediate between naïve CD4+ T cells and Tem. It has recently been proposed that the level of signal strength and γc containing cytokines play a role in memory T cell generation. However, little is known whether IL-12 or IL-23 are necessary and for this differentiation and/or maintenance. Our laboratory has previously described a patient with IL-12Rβ1 deficiency, which ablates both IL-12 and IL-23 signaling. This patient had a deficiency in Tem number and function, unexpectedly suggesting that IL-12 and/or IL-23 may play a key role in this process. We therefore hypothesized that signaling through IL-12Rβ1 plays a key role in the latter stages of generation and/or maintenance of human memory CD4+ T cells. Preliminary data thus far show CCR7 expression to be slightly decreased on activated Tcm in response to incubation with IL-2 or IL-12 alone, and to a greater extent with IL-2 and IL-12 incubated together. In addition, spontaneous apoptosis of both Tcm and Tem is decreased upon incubation with IL-12. Taken together, these data suggest that IL-12 may play a role in both generation of Tem and maintenance of both Tcm and Tem.

Download Full-text

Virus-Specific CD4+ T Cells Have Functional and Phenotypic Characteristics of Follicular T-Helper Cells in Patients With Acute and Chronic HCV Infections

Gastroenterology ◽

10.1053/j.gastro.2015.11.005 ◽

2016 ◽

Vol 150 (3) ◽

pp. 696-706.e3 ◽

Cited By ~ 45

Author(s):

Bijan Raziorrouh ◽

Kathrin Sacher ◽

Rajiv G. Tawar ◽

Florian Emmerich ◽

Christoph Neumann-Haefelin ◽

...

Keyword(s):

T Cells ◽

T Helper Cells ◽

Cd4 T Cells ◽

T Helper ◽

Phenotypic Characteristics ◽

Helper Cells ◽

Chronic Hcv ◽

Follicular T Helper Cells

Download Full-text

CD4 T cells specific for factor VIII are present at high frequency in healthy donors and comprise naïve and memory cells

Blood Advances ◽

10.1182/bloodadvances.2017008706 ◽

2017 ◽

Vol 1 (21) ◽

pp. 1842-1847 ◽

Cited By ~ 12

Author(s):

Sylvain Meunier ◽

Catherine Menier ◽

Elodie Marcon ◽

Sébastien Lacroix-Desmazes ◽

Bernard Maillère

Keyword(s):

T Cells ◽

Factor Viii ◽

High Frequency ◽

Cd4 T Cells ◽

Thymic Selection ◽

Memory Cells ◽

Central Tolerance ◽

Healthy Donors ◽

Key Points

Key Points Many CD4 T cells specific for FVIII escape thymic selection in healthy donors, revealing a low central tolerance to FVIII. Some FVIII-specific CD4 T cells are differentiated into memory cells but do not expand.

Download Full-text

Allosensitized Memory CD4 T Cells Induce Chronic Graft Versus Host Disease.

Blood ◽

10.1182/blood.v108.11.449.449 ◽

2006 ◽

Vol 108 (11) ◽

pp. 449-449 ◽

Cited By ~ 1

Author(s):

Suparna Dutt ◽

Diane Tseng ◽

Tracy I. George ◽

Joerg Ermann ◽

Yinping Liu ◽

...

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Chronic Gvhd ◽

T Cell Subsets ◽

Effector Memory ◽

Mouse Bone Marrow ◽

Memory Cells ◽

Activation Markers ◽

Effector Memory Cells ◽

Memory Cd4 T Cells

Abstract It has been reported that naive CD4+CD62LhiCD44lo T cells induce severe GVHD in a complete MHC mismatched allogeneic model of mouse bone marrow transplantation (BMT), but that effector memory CD4+CD62LloCD44hi T cells obtained from normal donors do not induce GVHD. The lack of GVHD-inducing capacity of effector memory cells from unprimed donors may reflect their lack of previous exposure to host alloantigens. We tested this hypothesis in a complete MHC mismatched allogeneic model of BMT by comparing the ability of effector memory T cells obtained from untreated C57BL/6 donors and donors immunized against host BALB/C alloantigens to induce GVHD. C57BL/6 donors were immunized by injecting 50 x106 host BALB/C spleen cells i.p. and after one week with 10x 106 cells. Both the unprimed and alloantigen primed CD4+ T cells expressed similar levels of lymph node homing chemokine receptor CCR7, and activation markers like CD69 and CD25. We sorted naive (CD62LhiCD44lo) and effector memory (CD62LloCD44hi) CD4+ T cell subsets from C57BL/6 donor mice four weeks after immunization, and compared their alloreactivity to BALB/C in an in vitro MLR. Interestingly effector memory CD4+ T cells from primed mice produced significantly higher levels of IFNγ compared to the effector memory from unprimed donors. We found that CD62LloCD44hi cells from unimmunized donors failed to induce GVHD in 85% of the hosts over 100 days while CD62LloCD44hi cells from immunized donors caused progressive weight loss and death in 100% of hosts (p <0.001). Whereas naive CD4+ T cells from unimmunized donors accumulated rapidly in the lymph nodes and spleen of irradiated hosts, effector memory CD4+ T cells had markedly reduced accumulation in these tissues. Furthermore, at day 6 after transplantation effector memory CD4+ T cells from primed mice, showed hundred fold higher accumulation in the host liver compared to unprimed effector memory donor CD4+ T cells. Long term surviving hosts transplanted with primed effector memory cells showed histopathological features of chronic GVHD in liver characterized by portal tract inflammation and lymphocyte infiltration with bile duct injury. In conclusion, memory CD4+ T cells from donors immunized to host alloantigens are able to induce chronic GVHD , but memory cells from unimmunized donors do not.

Download Full-text

The sensitivity of IL-4 production for cAMP inducers is lost in CD4+ T cells from aged mice

International Immunology ◽

10.1093/intimm/5.9.1167 ◽

1993 ◽

Vol 5 (9) ◽

pp. 1167-1176 ◽

Cited By ~ 5

Author(s):

Ruud Dobber ◽

Paula van den Bergh ◽

Margret Tielemans ◽

Joost Schuitemaker ◽

Lex Nageikerken

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Aged Mice

Download Full-text

CD4+ T cells that enter the draining lymph nodes after antigen injection participate in the primary response and become central–memory cells

Journal of Experimental Medicine ◽

10.1084/jem.20051954 ◽

2006 ◽

Vol 203 (4) ◽

pp. 1045-1054 ◽

Cited By ~ 117

Author(s):

Drew M. Catron ◽

Lori K. Rusch ◽

Jason Hataye ◽

Andrea A. Itano ◽

Marc K. Jenkins

Keyword(s):

T Cells ◽

Lymph Nodes ◽

Cd4 T Cells ◽

Primary Response ◽

Central Memory ◽

Secondary Response ◽

Memory Cells ◽

Mhc Ii ◽

Central Memory Cells ◽

Draining Lymph Nodes

We explored the relationship between the time of naive CD4+ T cell exposure to antigen in the primary immune response and the quality of the memory cells produced. Naive CD4+ T cells that migrated into the skin-draining lymph nodes after subcutaneous antigen injection accounted for about half of the antigen-specific population present at the peak of clonal expansion. These late-arriving T cells divided less and more retained the central–memory marker CD62L than the T cells that resided in the draining lymph nodes at the time of antigen injection. The fewer cell divisions were related to competition with resident T cells that expanded earlier in the response and a reduction in the number of dendritic cells displaying peptide–major histocompatibility complex (MHC) II complexes at later times after antigen injection. The progeny of late-arriving T cells possessed the phenotype of central–memory cells, and proliferated more extensively during the secondary response than the progeny of the resident T cells. The results suggest that late arrival into lymph nodes and exposure to antigen-presenting cells displaying lower numbers of peptide–MHC II complexes in the presence of competing T cells ensures that some antigen-specific CD4+ T cells divide less in the primary response and become central–memory cells.

Download Full-text

CD95 Expression in Aged Mice Infected with Tuberculosis

Infection and Immunity ◽

10.1128/iai.66.10.5036-5040.1998 ◽

1998 ◽

Vol 66 (10) ◽

pp. 5036-5040 ◽

Cited By ~ 5

Author(s):

A. D. Roberts ◽

Ian M. Orme

Keyword(s):

T Cells ◽

Mycobacterium Tuberculosis ◽

Cd4 T Cells ◽

Activated T Cells ◽

Homeostatic Mechanism ◽

Aged Mice ◽

Induction Of Apoptosis ◽

Old Mice

ABSTRACT The interaction between CD95 and its ligand is an important homeostatic mechanism that leads to the induction of apoptosis in activated T cells. In view of recent evidence that this pathway might be defective in aged mice, this study investigated CD95 expression on T cells in old mice activated by infection with Mycobacterium tuberculosis. The results of the study do not support the hypothesis that CD95 is poorly expressed on CD4 T cells from old mice; instead, it was found that similar numbers of T cells from young and old mice expressed CD95, with the intensity of expression if anything higher on the cells from the old mice. In addition, the study demonstrated that changes in CD44 and CD45RB expression previously observed in young infected mice proceeded in a similar fashion in old animals and, as would be predicted, that CD95hi expression was primarily associated with CD4 T cells expressing the activated CD44hi CD45RBhi phenotype.

Download Full-text