Gut memories do not fade: epigenetic regulation of lasting gut homing receptor expression in CD4+ memory T cells

Human T helper (Th) cells (Th1- or Th2-oriented memory T cells as well as Th1- or Th2-polarized naive T cells) were infected in vitro with an R5-tropic HIV-1 strain (BaL) and assessed for their profile of cytokine production, CCR5 receptor expression, and HIV-1 p24 antigen (p24 Ag) production. Higher p24 Ag production was found in CCR5-negative Th2-like memory T cells than in CCR5-positive Th1-like memory T cells. By contrast, p24 Ag production was higher in Th1-polarized activated naive T cells in the first 4 days after infection. However, p24 Ag production in Th1-polarized T cells became comparable or even lower than the production in Th2-polarized populations later in infection or when the cells were infected with HIV-1BaL after secondary stimulation. The higher levels of p24 Ag production by Th1-polarized naive T cells soon after infection reflected a higher virus entry, as assessed by the single round infection assay using the HIV–chloramphenicol acetyl transferase (HIV-CAT) R5-tropic virus that contains the envelope protein of HIV-1 YU2 strain. The limitation of viral spread in the Th1-polarized populations, despite the initial higher level of T-cell entry of R5-tropic strains, was due to the ability of Th1 cells to produce greater amounts of β-chemokines than Th2 cells. In fact, an inverse correlation was observed between Th1-polarized naive T cells and Th1-like memory-activated T cells in regards to p24 Ag production and the release of the following CCR5-binding chemokines: regulated on activation normal T expressed and secreted (RANTES), macrophage inflammatory protein–1 (MIP-1), and MIP-1β. Moreover, infection with the HIV-1BaL strain of Th1-polarized T cells in the presence of a mixture of anti-RANTES, anti–MIP-1, and anti–MIP-1β neutralizing antibodies resulted in a significant increase of HIV-1 expression. These findings suggest that Th1-type responses may favor CD4+ T-cell infection by R5-tropic HIV-1 strains, but HIV-1 spread in Th1 cells is limited by their ability to produce CCR5-binding chemokines.

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Innate Immune Responses to Herpes Simplex Virus Type 2 Influence Skin Homing Molecule Expression by Memory CD4+ Lymphocytes

Journal of Virology ◽

10.1128/jvi.80.6.2863-2872.2006 ◽

2006 ◽

Vol 80 (6) ◽

pp. 2863-2872 ◽

Cited By ~ 12

Author(s):

David M. Koelle ◽

Jay Huang ◽

Michael T. Hensel ◽

Christopher L. McClurkan

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Cd4 T Cells ◽

Receptor Expression ◽

Homing Receptor ◽

Skin Homing ◽

Simplex Virus

ABSTRACT Herpes simplex virus (HSV) infections of humans are characterized by intermittent, lytic replication in epithelia. Circulating HSV-specific CD4 T cells express lower levels of preformed cutaneous lymphocyte-associated antigen (CLA), a skin-homing receptor, than do circulating HSV-specific CD8 T cells but, paradoxically, move into infected skin earlier than CD8 cells. Memory CD4 T cells develop strong and selective expression of CLA and E-selectin ligand while responding to HSV antigen in vitro. We now show that interleukin-12, type I interferon, and transforming growth factor beta are each involved in CLA expression by memory HSV type 2 (HSV-2)-specific CD4 T cells in peripheral blood mononuclear cells (PBMC). A reduction of the number of monocytes and dendritic cells from PBMC reduces CLA expression by HSV-2-responsive CD4 lymphoblasts, while their reintroduction restores this phenotype, identifying these cells as possible sources of CLA-promoting cytokines. Plasmacytoid dendritic cells are particularly potent inducers of CLA on HSV-reactive CD4 T cells. These observations are consistent with cooperation between innate and acquired immunity to promote a pattern of homing receptor expression that is physiologically appropriate for trafficking to infected tissues.

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Epidermis instructs skin homing receptor expression in human T cells

Blood ◽

10.1182/blood-2012-05-433037 ◽

2012 ◽

Vol 120 (23) ◽

pp. 4591-4598 ◽

Cited By ~ 56

Author(s):

Michelle L. McCully ◽

Kristin Ladell ◽

Svetlana Hakobyan ◽

Robert E. Mansel ◽

David A. Price ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Human Skin ◽

Memory T Cells ◽

Immune Surveillance ◽

Receptor Expression ◽

Epidermal Keratinocytes ◽

Specific Factor ◽

Peripheral Tissues ◽

Preferential Expression

Abstract The localization of memory T cells to human skin is essential for long-term immune surveillance and the maintenance of barrier integrity. Although the mechanisms controlling memory T-cell migration to peripheral tissues are poorly understood, the current paradigm includes the localized secretion of “imprinting” signals from tissue-resident dendritic cells in the draining lymph nodes. Here we show that CCR8 expression by newly activated naive T cells is regulated by skin-specific factor(s) derived primarily from epidermal keratinocytes, thereby providing a mechanism for the preferential expression of CCR8 by skin-resident memory T cells. Importantly, no such effects were observed after coculture with primary cells from skin-unrelated epithelia, including mesothelium and small intestine. The keratinocyte-derived CCR8-inducing factor(s) were soluble, and independent of vitamins A and D. Furthermore, the induction of CCR8 under these conditions correlated with an increase in cutaneous lymphocyte-associated antigen expression. Our findings challenge current tissue homing paradigms, especially those involving CCR10, and emphasize the importance of steady-state epidermis rather than tissue-resident dendritic cells in controlling the localization of memory T cells within human skin.

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IL-7 Receptor Expression Provides the Potential for Long-Term Survival of Both CD62Lhigh Central Memory T Cells and Th1 Effector Cells during Leishmania major Infection

The Journal of Immunology ◽

10.4049/jimmunol.0803450 ◽

2009 ◽

Vol 182 (9) ◽

pp. 5702-5711 ◽

Cited By ~ 33

Author(s):

Sara L. Colpitts ◽

Nicole M. Dalton ◽

Phillip Scott

Keyword(s):

T Cells ◽

Leishmania Major ◽

Memory T Cells ◽

Receptor Expression ◽

Term Survival ◽

Long Term Survival ◽

Effector Cells ◽

Major Infection ◽

Central Memory T Cells

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Skin-versus gut-skewed homing receptor expression and intrinsic CCR4 expression on human peripheral blood CD4+CD25+ suppressor T cells

European Journal of Immunology ◽

10.1002/eji.200323658 ◽

2003 ◽

Vol 33 (6) ◽

pp. 1488-1496 ◽

Cited By ~ 80

Author(s):

Andrea Iellem ◽

Lucia Colantonio ◽

Daniele D'Ambrosio

Keyword(s):

T Cells ◽

Peripheral Blood ◽

Human Peripheral Blood ◽

Receptor Expression ◽

Suppressor T Cells ◽

Homing Receptor

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Oral Immunization with a Salmonella enterica Serovar Typhi Vaccine Induces Specific Circulating Mucosa-Homing CD4+ and CD8+ T Cells in Humans

Infection and Immunity ◽

10.1128/iai.70.10.5622-5627.2002 ◽

2002 ◽

Vol 70 (10) ◽

pp. 5622-5627 ◽

Cited By ~ 75

Author(s):

B. Samuel Lundin ◽

Camilla Johansson ◽

Ann-Mari Svennerholm

Keyword(s):

T Cells ◽

Vaccine Strain ◽

Salmonella Enterica ◽

Magnetic Beads ◽

Memory T Cells ◽

Oral Immunization ◽

Receptor Expression ◽

Ifn Γ ◽

Almost All

ABSTRACT The kinetics and homing characteristics of T-cell responses in humans after mucosal immunizations have not been well characterized. Therefore, we have investigated the magnitude and duration of such responses as well as the homing receptor expression of antigen-specific peripheral blood T cells by using an oral model vaccine, i.e., the live, attenuated Salmonella enterica serovar Typhi vaccine (Ty21a). Eight volunteers were each given three doses of the vaccine 2 days apart, and blood samples, from which CD4+ and CD8+ T cells were selected by the use of magnetic beads, were collected before vaccination and at regular intervals thereafter. To purify the potentially antigen-specific gut-homing T cells, CD45RA− integrin β7 + cells were further sorted by flow cytometry. The sorted cells were then stimulated in vitro with the serovar Typhi vaccine strain, and the proliferation of cells and the cytokine production were measured. Following vaccination, there was a large increase in both the proliferation of and the gamma interferon (IFN-γ) production by blood T cells stimulated with the vaccine strain. The responses were seen among both CD4+ and CD8+ T cells, although the CD8+ cells produced the largest amounts of IFN-γ. Peak responses were seen 7 to 14 days after the onset of vaccination. Furthermore, most of the IFN-γ produced by both CD4+ and CD8+ cells emanated from cells with the potential to home to mucosal tissues, as the integrin β7-expressing memory T cells produced around 10-fold more IFN-γ than the remaining populations. In conclusion, we demonstrate that oral vaccination with a live oral bacterial vaccine induces antigen-specific CD4+ and CD8+ memory T cells, almost all of which express the gut-homing integrin β7.

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Dynamic Development of Homing Receptor Expression and Memory Cell Differentiation of Infant CD4+CD25high Regulatory T Cells

The Journal of Immunology ◽

10.4049/jimmunol.0901091 ◽

2009 ◽

Vol 183 (7) ◽

pp. 4360-4370 ◽

Cited By ~ 72

Author(s):

Hanna Grindebacke ◽

Hanna Stenstad ◽

Marianne Quiding-Järbrink ◽

Jesper Waldenström ◽

Ingegerd Adlerberth ◽

...

Keyword(s):

T Cells ◽

Cell Differentiation ◽

Regulatory T Cells ◽

Memory Cell ◽

Receptor Expression ◽

Homing Receptor ◽

Dynamic Development

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Circulating allergen-reactive T cells from patients with atopic dermatitis and allergic contact dermatitis express the skin-selective homing receptor, the cutaneous lymphocyte-associated antigen.

Journal of Experimental Medicine ◽

10.1084/jem.181.5.1935 ◽

1995 ◽

Vol 181 (5) ◽

pp. 1935-1940 ◽

Cited By ~ 205

Author(s):

L F Santamaria Babi ◽

L J Picker ◽

M T Perez Soler ◽

K Drzimalla ◽

P Flohr ◽

...

Keyword(s):

T Cells ◽

Atopic Dermatitis ◽

T Cell ◽

Contact Dermatitis ◽

Allergic Contact Dermatitis ◽

Memory T Cells ◽

Homing Receptor ◽

Memory T Cell ◽

Cell Responses ◽

Allergic Contact

The cutaneous lymphocyte-associated antigen (CLA) is the major T cell ligand for the vascular adhesion molecule E-selectin, and it has been proposed to be involved in the selective targeting of memory T cells reactive with skin-associated Ag to cutaneous inflammatory sites. To further investigate the relation of CLA and cutaneous T cell responses, we analyzed the CLA phenotype of circulating memory T cells in patients with allergic contact dermatitis and atopic dermatitis (AD) alone vs in patients manifesting bronchopulmonary atopy (asthma with or without AD) and nonallergic individuals. Significant T cell proliferative responses to Ni, a contact allergen, and to the house dust mite (HDM), an allergen to which sensitization is often observed in AD and/or asthma, was noted only in allergic and atopic individuals, respectively. When the minor circulating CLA+CD3+CD45RO+ subset was separated from the major CLA-CD3+CD45RO+ subpopulation in Ni-sensitive subjects, the Ni-dependent memory T cell response was largely confined to the CLA+ subset. A similar restriction of the T cell proliferative response to the CLA+ memory subset was observed for HDM in patients with AD alone. In HDM-sensitive patients with asthma with or without AD, however, the CLA- subset exhibited a strong antigen-dependent proliferation, in contrast to patients with AD alone, whose CLA- subset proliferated very weakly to HDM. In asthma with or without AD, the HDM-dependent proliferation slightly predominated in the CLA- when compared to the CLA+ subset. The functional linkage between CLA expression and disease-associated T cell effector function in AD was also demonstrated by the finding that the circulating CLA+ T cell subset in AD patients, but not nonatopic controls, selectively showed both evidence of prior activation (human histocompatibility antigen-DR expression) and spontaneous production of interleukin 4 but not interferon-gamma. Taken together, these observations demonstrate the correlation of CLA expression on circulating memory T cells and disease-associated memory T cell responses in cutaneous hypersensitivity, and they suggest the existence of mechanisms capable of sorting particular T cell Ag specificities and lymphokine patterns into homing receptor-defined memory subsets.

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