Developmental interactions of CD4 T cells and thymocytes: age-related differential effects

With increasing age, the ability to produce protective antibodies in response to immunization declines, leading to a reduced efficacy of vaccination in the elderly. To examine the effect of age on the cognate function of CD4 T cells, we have used a novel adoptive transfer model that allows us to compare identical numbers of antigen-specific naive T cells from young and aged TCR transgenic (Tg) donors. Upon transfer of aged donor CD4 T cells to young hosts, there was significantly reduced expansion and germinal center (GC) differentiation of the antigen-specific B cell population after immunization. This reduced cognate helper function was seen at all time points and over a wide range of donor cell numbers. In hosts receiving aged CD4 cells, there were also dramatically lower levels of antigen-specific IgG. These age-related defects were not due to defects in migration of the aged CD4 T cells, but may be attributable to reduced CD154 (CD40L) expression. Furthermore, we found that there was no difference in B cell expansion and differentiation or in IgG production when young CD4 T cells were transferred to young or aged hosts. Our results show that, in this model, age-related reductions in the cognate helper function of CD4 T cells contribute significantly to defects in humoral responses observed in aged individuals.

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Differential effects of IFN-α on the expression of various TH2 cytokines in human CD4+ T cells

Journal of Allergy and Clinical Immunology ◽

10.1016/j.jaci.2005.03.016 ◽

2005 ◽

Vol 116 (1) ◽

pp. 205-212 ◽

Cited By ~ 25

Author(s):

Hideki Shibuya ◽

Shunsei Hirohata

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Th2 Cytokines ◽

Differential Effects

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Age-related changes in CD4 T cells of T cell receptor transgenic mice

Mechanisms of Ageing and Development ◽

10.1016/s0047-6374(96)01826-x ◽

1997 ◽

Vol 93 (1-3) ◽

pp. 95-105 ◽

Cited By ~ 26

Author(s):

Laura Haynes ◽

Phyllis-Jean Linton ◽

Susan L Swain

Keyword(s):

T Cells ◽

T Cell ◽

Transgenic Mice ◽

T Cell Receptor ◽

Cd4 T Cells ◽

Cell Receptor ◽

Age Related ◽

Age Related Changes

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Age-related changes in lymphokine production related to a decreased number of CD45RBhi CD4+ T cells

European Journal of Immunology ◽

10.1002/eji.1830210206 ◽

1991 ◽

Vol 21 (2) ◽

pp. 273-281 ◽

Cited By ~ 123

Author(s):

Lex Nagelkerken ◽

Anita Hertogh-Huijbregts ◽

Ruud Dobber ◽

Angelika Dräger

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Lymphokine Production ◽

Age Related ◽

Age Related Changes

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Adaptive Immune Responses Mediated Age-related Plasmodium yoelii 17XL and 17XNL Infections in 4 and 8-week-old BALB/c Mice

10.21203/rs.2.15639/v1 ◽

2019 ◽

Author(s):

Qiu-bo Wang ◽

Yun-ting Du ◽

Fei Liu ◽

Xiao-dan Sun ◽

Xun Sun ◽

...

Keyword(s):

T Cells ◽

Survival Rate ◽

Cd4 T Cells ◽

Plasmodium Yoelii ◽

Th2 Cells ◽

Dependent Manner ◽

Adaptive Immune ◽

Age Related ◽

Ifn Γ ◽

Old Mice

Abstract Background As the quest to eradicate malaria continues, it is important to clarify the opposite clinical outcomes between childhood and adulthood. The relationship between adaptive immune response and age-related malaria infection remains unknown. Methods 4 and 8-week-old mice were used to mimic childhood and adulthood, respectively. Parasitemia and the survival rate were monitored. The proportion and function of Th1 and Th2 cells were detected by FACS. The levels of IFN-γ, IL-4, total IgG, IgG1, IgG2a and Plasmodium yoelii MSP-1-special IgG were measured by ELISA. Results Infant mice were more susceptible to P. yoelii 17XNL infection, with lower survival rate and higher parasitemia. The adult group showed greater resistance to P. yoelii 17XL infection, with lower parasitemia. Compared with 4-week-old mice, the percentage of CD4 + T-bet + IFN-γ + Th1 cells as well as IFN-γ production were significantly increased on day 5 p.i. in the 8-week-old mice after P. yoelii 17XNL infection. The percentage of CD4 + GATA3 + IL-4 + Th2 cells and CD4 + CXCR5 + Tfh cells, and IL-4 production in the 8-week-old mice obviously increased on day 5 and day 10 after P. yoelii 17XNL infection. Notably, the levels of total IgG, IgG1, IgG2a and P. yoelii MSP-1-special IgG were also significantly increased in the 8-week-old mice. PD-1, a marker of exhaustion, was up-regulated on CD4 + or activated CD4 + T cells in the 8-week-old mice as compared to the 4-week-old group. Conclusion We consider that enhanced cellular and humoral adaptive immunity might contribute to rapid clearance of malaria among adults, likely in a PD-1-dependent manner due to induction of CD4 + T cells exhaustion.

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Age-related changes in lck–Vav signaling pathways in mouse CD4 T cells

Cellular Immunology ◽

10.1016/j.cellimm.2009.06.001 ◽

2009 ◽

Vol 259 (1) ◽

pp. 100-104 ◽

Cited By ~ 7

Author(s):

Gonzalo G. Garcia ◽

Richard A. Miller

Keyword(s):

T Cells ◽

Signaling Pathways ◽

Cd4 T Cells ◽

Age Related ◽

Age Related Changes

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Age-Related Induction of CD4+ T-Cell Unresponsiveness Is Reversible and Dependant of the Host’s Environment.

Blood ◽

10.1182/blood.v106.11.3925.3925 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3925-3925

Author(s):

Pedro Horna ◽

Rahul Chavan ◽

Jason Brayer ◽

Ildefonso Suarez ◽

Eduardo M. Sotomayor

Keyword(s):

T Cells ◽

T Cell ◽

Transgenic Mice ◽

Cd4 T Cells ◽

Cd4 T Cell ◽

Cell Compartment ◽

Memory Phenotype ◽

Age Related ◽

And Function

Abstract A large number of CD4+ T-cells from either aged mice or humans display surface markers associated with an activated/memory phenotype. In spite of these changes however, these T-cells have a markedly decreased ability to proliferate and produce IL-2 in response to antigen stimulation in vitro. The cellular and molecular mechanisms involved in this age-related unresponsiveness of the CD4+ T-cell compartment remain poorly understood. Utilizing a well-established experimental system in which transgenic CD4+ T cells specific for a MHC class II restricted epitope of influenza hemagglutinin (HA) are adoptively transferred into non-transgenic recipients, we have previously elucidated important mechanisms involved in the induction and maintenance of CD4+ T-cell tolerance. Our studies were however limited to the analysis of T-cell function in lymphoma bearing young mice (4 to 10 weeks old). Here, we assessed the influence of the aged microenvironment in determining the phenotype and function of antigen-specific T-cells. CD4+ T-cells from young TCR transgenic mice (2 months old) were adoptively transferred into either old (20–24 months) or young (2 months old) non-transgenic mice. Two weeks later, clonotypic and non-clonotypic CD4+ T-cells were isolated from the spleens of these animals and their phenotype and function were determined in vitro. Reminiscent of the age-related changes observed within the normal CD4+ T-cell repertoire, young transgenic T-cells transferred into aged hosts have acquired an activated/memory phenotype but displayed a significant impairment in antigen-specific proliferation and IL-2 production in response to cognate antigen in vitro. These changes were not due to homeostatic proliferation of the transferred T-cells into the relatively lymphopenic aged host. To determine whether the changes observed in “aged” T-cells were reversible or not, we adoptively transfer old T-cells back into young hosts or into control old mice. While old transgenic T-cells transferred into an old environment remained fully unresponsive, the adoptive transfer of the same old T-cells into a young host restored their ability to proliferate and produce IL-2. Surprisingly, these “old” T-cells were able to produce significantly higher levels of IFN-gamma indicative of their memory/effector phenotype. Furthermore, young animals adoptively transferred with “aged” antigen-specific T-cells were now capable of rejecting A20 B-cell lymphomas expressing HA as a model tumor antigen (A20HA). Taking together, factor(s) present in the aged microenvironment are responsible for limiting the effector function of CD4+ T-cells that seem otherwise well equipped to become fully activated if the proper environment is provided (young microenvironment). The potential role of soluble suppressive factors as well as regulatory T-cells (Tregs) in the unresponsiveness observed in the T-cell compartment of aged hosts will be discussed.

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