Increased expression of Suppressor of Cytokine Signaling‐1 (SOCS‐1) by dendritic and CD4+ T cells of HIV‐1 transgenic rats: A mechanism for dysregulated T helper‐1 responses

Abstract Defects of the common gamma chain subunit of the cytokine receptors (γc) or of Jak3, a tyrosine kinase required for γc signal transduction, result in T−B+ severe combined immunodeficiency (SCID). However, atypical cases, characterized by progressive development of T lymphocytes, have been also reported. We describe a child with SCID caused by Jak3 gene defects, which strongly but not completely affect Jak3 protein expression and function, who developed a substantial number (>3,000/μL) of autologous CD3+CD4+ T cells. These cells showed a primed/activated phenotype (CD45R0+ Fas+HLA-DR+ CD62Llo), defective secretion of T-helper 1 and T-helper 2 cytokines, reduced proliferation to mitogens, and a high in vitro susceptibility to spontaneous (caused by downregulation of bcl-2 expression) as well as activation-induced cell death. A restricted T-cell receptor repertoire was observed, with oligoclonal expansion within each of the dominant segments. These features resemble those observed in γc-/y and in Jak3−/−mice, in which a population of activated, anergic T cells (predominantly CD4+) also develops with age. These results suggest that residual Jak3 expression and function or other Jak3-independent signals may also permit the generation of CD4+ T cells that undergo in vivo clonal expansion in humans; however, these mechanisms do not allow development of CD8+ T cells, nor do they fully restore the functional properties of CD4+ T lymphocytes.

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CD4+T Cells: Differentiation and Functions

Clinical and Developmental Immunology ◽

10.1155/2012/925135 ◽

2012 ◽

Vol 2012 ◽

pp. 1-12 ◽

Cited By ~ 341

Author(s):

Rishi Vishal Luckheeram ◽

Rui Zhou ◽

Asha Devi Verma ◽

Bing Xia

Keyword(s):

T Cells ◽

Transcription Factors ◽

T Cell ◽

Cytokine Signaling ◽

T Helper ◽

T Helper 1 ◽

T Helper 17 ◽

Differentiated Cells ◽

Follicular Helper ◽

Follicular Helper T Cell

CD4+T cells are crucial in achieving a regulated effective immune response to pathogens. Naive CD4+T cells are activated after interaction with antigen-MHC complex and differentiate into specific subtypes depending mainly on the cytokine milieu of the microenvironment. Besides the classical T-helper 1 and T-helper 2, other subsets have been identified, including T-helper 17, regulatory T cell, follicular helper T cell, and T-helper 9, each with a characteristic cytokine profile. For a particular phenotype to be differentiated, a set of cytokine signaling pathways coupled with activation of lineage-specific transcription factors and epigenetic modifications at appropriate genes are required. The effector functions of these cells are mediated by the cytokines secreted by the differentiated cells. This paper will focus on the cytokine-signaling and the network of transcription factors responsible for the differentiation of naive CD4+T cells.

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AttenuatedListeria monocytogenescarrier strains can deliver an HIV-1 gp120 T helper epitope to MHC class II-restricted human CD4+ T cells

European Journal of Immunology ◽

10.1002/(sici)1521-4141(199806)28:06<1807::aid-immu1807>3.0.co;2-w ◽

1998 ◽

Vol 28 (6) ◽

pp. 1807-1814 ◽

Cited By ~ 16

Author(s):

Carlos A. Guzmán ◽

Daniele Saverino ◽

Eva Medina ◽

Daniela Fenoglio ◽

Birgit Gerstel ◽

...

Keyword(s):

T Cells ◽

Mhc Class Ii ◽

Cd4 T Cells ◽

Class Ii ◽

T Helper ◽

Helper Epitope ◽

Hiv 1

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Adenovirus Serotype 5 Vaccination Results in Suboptimal CD4 T Helper 1 Responses in Mice

Journal of Virology ◽

10.1128/jvi.01132-16 ◽

2016 ◽

Vol 91 (5) ◽

Cited By ~ 7

Author(s):

Junghwa Lee ◽

Masao Hashimoto ◽

Se Jin Im ◽

Koichi Araki ◽

Hyun-Tak Jin ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

T Cell Responses ◽

Cd4 T Cell ◽

T Helper ◽

T Helper 1 ◽

Cell Responses ◽

Serotype 5 ◽

Lcmv Infection

ABSTRACT Adenovirus serotype 5 (Ad5) is one of the most widely used viral vectors and is known to generate potent T cell responses. While many previous studies have characterized Ad5-induced CD8 T cell responses, there is a relative lack of detailed studies that have analyzed CD4 T cells elicited by Ad5 vaccination. Here, we immunized mice with Ad5 vectors encoding lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) and examined GP-specific CD4 T cell responses elicited by Ad5 vectors and compared them to those induced by an acute LCMV infection. In contrast to LCMV infection, where balanced CD4 T helper 1 (Th1) and T follicular helper (Tfh) responses were induced, Ad5 immunization resulted in a significantly reduced frequency of Th1 cells. CD4 T cells elicited by Ad5 vectors expressed decreased levels of Th1 markers, such as Tim3, SLAM, T-bet, and Ly6C, had smaller amounts of cytotoxic molecules like granzyme B, and produced less interferon gamma than CD4 T cells induced by LCMV infection. This defective CD4 Th1 response appeared to be intrinsic for Ad5 vectors and not a reflection of comparing a nonreplicating vector to a live viral infection, since immunization with a DNA vector expressing LCMV-GP generated efficient CD4 Th1 responses. Analysis at early time points (day 3 or 4) after immunization with Ad5 vectors revealed a defect in the expression of CD25 (interleukin-2 [IL-2] receptor alpha chain) on Ad5-elicited CD4 T cells, and administration of exogenous IL-2 following Ad5 immunization partially restored CD4 Th1 responses. These results suggest that impairment of Th1 commitment after Ad5 immunization could be due to reduced IL-2-mediated signaling. IMPORTANCE During viral infection, generating balanced responses of Th1 and Tfh cells is important to induce effective cell-mediated responses and provide optimal help for antibody responses. In this study, to investigate vaccine-induced CD4 T cell responses, we characterized CD4 T cells after immunization with Ad5 vectors expressing LCMV-GP in mice. Ad5 vectors led to altered effector differentiation of LCMV GP-specific CD4 T cells compared to that during LCMV infection. CD4 T cells following Ad5 immunization exhibited impaired Th1 lineage commitment, generating significantly decreased Th1 responses than those induced by LCMV infection. Our results suggest that suboptimal IL-2 signaling possibly plays a role in reduced Th1 development following Ad5 immunization.

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Development of Autologous, Oligoclonal, Poorly Functioning T Lymphocytes in a Patient With Autosomal Recessive Severe Combined Immunodeficiency Caused by Defects of the Jak3 Tyrosine Kinase

Blood ◽

10.1182/blood.v91.3.949.949_949_955 ◽

1998 ◽

Vol 91 (3) ◽

pp. 949-955 ◽

Cited By ~ 1

Author(s):

Duilio Brugnoni ◽

Luigi D. Notarangelo ◽

Alessandra Sottini ◽

Paolo Airò ◽

Marta Pennacchio ◽

...

Keyword(s):

T Cells ◽

T Lymphocytes ◽

Tyrosine Kinase ◽

Cd4 T Cells ◽

Severe Combined Immunodeficiency ◽

Combined Immunodeficiency ◽

T Helper ◽

T Helper 1 ◽

In Vitro Susceptibility ◽

And Function

Defects of the common gamma chain subunit of the cytokine receptors (γc) or of Jak3, a tyrosine kinase required for γc signal transduction, result in T−B+ severe combined immunodeficiency (SCID). However, atypical cases, characterized by progressive development of T lymphocytes, have been also reported. We describe a child with SCID caused by Jak3 gene defects, which strongly but not completely affect Jak3 protein expression and function, who developed a substantial number (>3,000/μL) of autologous CD3+CD4+ T cells. These cells showed a primed/activated phenotype (CD45R0+ Fas+HLA-DR+ CD62Llo), defective secretion of T-helper 1 and T-helper 2 cytokines, reduced proliferation to mitogens, and a high in vitro susceptibility to spontaneous (caused by downregulation of bcl-2 expression) as well as activation-induced cell death. A restricted T-cell receptor repertoire was observed, with oligoclonal expansion within each of the dominant segments. These features resemble those observed in γc-/y and in Jak3−/−mice, in which a population of activated, anergic T cells (predominantly CD4+) also develops with age. These results suggest that residual Jak3 expression and function or other Jak3-independent signals may also permit the generation of CD4+ T cells that undergo in vivo clonal expansion in humans; however, these mechanisms do not allow development of CD8+ T cells, nor do they fully restore the functional properties of CD4+ T lymphocytes.

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Loss of HIV-1–specific CD8+ T Cell Proliferation after Acute HIV-1 Infection and Restoration by Vaccine-induced HIV-1–specific CD4+ T Cells

Journal of Experimental Medicine ◽

10.1084/jem.20041270 ◽

2004 ◽

Vol 200 (6) ◽

pp. 701-712 ◽

Cited By ~ 267

Author(s):

Mathias Lichterfeld ◽

Daniel E. Kaufmann ◽

Xu G. Yu ◽

Stanley K. Mui ◽

Marylyn M. Addo ◽

...

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Chronic Infection ◽

Cell Function ◽

Acute Infection ◽

T Helper Cell ◽

T Helper ◽

Functional Defect ◽

Hiv 1

Virus-specific CD8+ T cells are associated with declining viremia in acute human immunodeficiency virus (HIV)1 infection, but do not correlate with control of viremia in chronic infection, suggesting a progressive functional defect not measured by interferon γ assays presently used. Here, we demonstrate that HIV-1–specific CD8+ T cells proliferate rapidly upon encounter with cognate antigen in acute infection, but lose this capacity with ongoing viral replication. This functional defect can be induced in vitro by depletion of CD4+ T cells or addition of interleukin 2–neutralizing antibodies, and can be corrected in chronic infection in vitro by addition of autologous CD4+ T cells isolated during acute infection and in vivo by vaccine-mediated induction of HIV-1–specific CD4+ T helper cell responses. These data demonstrate a loss of HIV-1–specific CD8+ T cell function that not only correlates with progressive infection, but also can be restored in chronic infection by augmentation of HIV-1–specific T helper cell function. This identification of a reversible defect in cell-mediated immunity in chronic HIV-1 infection has important implications for immunotherapeutic interventions.

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