Efficacy of clonal deletion vs. anergy of self-reactive CD4 T-cells for the prevention and reversal of autoimmune diabetes

Chronic viral infections subvert protective B cell immunity. An early type I interferon (IFN-I)–driven bias to short-lived plasmablast differentiation leads to clonal deletion, so-called “decimation,” of antiviral memory B cells. Therefore, prophylactic countermeasures against decimation remain an unmet need. We show that vaccination-induced CD4 T cells prevented the decimation of naïve and memory B cells in chronically lymphocytic choriomeningitis virus (LCMV)-infected mice. Although these B cell responses were largely T independent when IFN-I was blocked, preexisting T help assured their sustainability under conditions of IFN-I–driven inflammation by instructing a germinal center B cell transcriptional program. Prevention of decimation depended on T cell–intrinsic Bcl6 and Tfh progeny formation. Antigen presentation by B cells, interactions with antigen-specific T helper cells, and costimulation by CD40 and ICOS were also required. Importantly, B cell–mediated virus control averted Th1-driven immunopathology in LCMV-challenged animals with preexisting CD4 T cell immunity. Our findings show that vaccination-induced Tfh cells represent a cornerstone of effective B cell immunity to chronic virus challenge, pointing the way toward more effective B cell–based vaccination against persistent viral diseases.

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Hybrid insulin peptides are neo-epitopes for CD4 T cells in autoimmune diabetes

Current Opinion in Endocrinology Diabetes and Obesity ◽

10.1097/med.0000000000000490 ◽

2019 ◽

Vol 26 (4) ◽

pp. 195-200

Author(s):

Rocky L. Baker ◽

Braxton L. Jamison ◽

Kathryn Haskins

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Autoimmune Diabetes

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Autoimmune diabetes can be induced in transgenic major histocompatibility complex class II-deficient mice.

Journal of Experimental Medicine ◽

10.1084/jem.178.2.589 ◽

1993 ◽

Vol 178 (2) ◽

pp. 589-596 ◽

Cited By ~ 29

Author(s):

T M Laufer ◽

M G von Herrath ◽

M J Grusby ◽

M B Oldstone ◽

L H Glimcher

Keyword(s):

T Cells ◽

Major Histocompatibility Complex ◽

Mhc Class Ii ◽

Cd4 T Cells ◽

Islet Cells ◽

Autoimmune Diabetes ◽

Class Ii ◽

Dependent Diabetes Mellitus ◽

Major Histocompatibility ◽

Histocompatibility Complex

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease marked by hyperglycemia and mononuclear cell infiltration of insulin-producing beta islet cells. Predisposition to IDDM in humans has been linked to the class II major histocompatibility complex (MHC), and islet cells often become aberrantly class II positive during the course of the disease. We have used two recently described transgenic lines to investigate the role of class II molecules and CD4+ T cells in the onset of autoimmune insulitis. Mice that are class II deficient secondary to a targeted disruption of the A beta b gene were bred to mice carrying a transgene for the lymphocytic choriomenigitis virus (LCMV) glycoprotein (GP) targeted to the endocrine pancreas. Our results indicate that class II-deficient animals with and without the GP transgene produce a normal cytotoxic T lymphocyte response to whole LCMV. After infection with LCMV, GP-transgenic class II-deficient animals develop hyperglycemia as rapidly as their class II-positive littermates. Histologic examination of tissue sections from GP-transgenic class II-deficient animals reveals lymphocytic infiltrates of the pancreatic islets that are distinguishable from those of their class II-positive littermates only by the absence of infiltrating CD4+ T cells. These results suggest that in this model of autoimmune diabetes, CD4+ T cells and MHC class II molecules are not required for the development of disease.

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Neonatal deletion and selective expansion of mouse T cells by exposure to rabies virus nucleocapsid superantigen.

Journal of Experimental Medicine ◽

10.1084/jem.180.4.1207 ◽

1994 ◽

Vol 180 (4) ◽

pp. 1207-1215 ◽

Cited By ~ 34

Author(s):

M Lafon ◽

D Scott-Algara ◽

P N Marche ◽

P A Cazenave ◽

E Jouvin-Marche

Keyword(s):

T Cells ◽

Rabies Virus ◽

Cd4 T Cells ◽

Present Report ◽

Cell Receptor ◽

Repeated Injection ◽

Clonal Deletion ◽

Virus Component ◽

Dose Dependent ◽

Draining Lymph Nodes

The nucleocapsid (NC) of the rabies virus behaves as an exogenous superantigen (SAg) in humans. In the present report, we analyzed whether it is also a SAg in mice by studying the effect of NC on T cell receptor (TCR) V beta expression in BALB/c mice. Repeated injection of NC in newborn BALB/c mice led to a marked reduction by two- to sixfold of V beta 6 expressing CD4+ T cells in spleen and in peripheral blood. Decrease of V beta 6-expressing CD3+ mature T cells was also observed in thymus. Single NC injection in footpad resulted in a three- to sixfold expansion of V beta 6 CD4+ T cells, but not of CD8+ T cells, in the draining lymph nodes of BALB/c mice. The intensity of the stimulation was dose dependent and was maximal 3 d after the NC injection. The clonal deletion of T cells bearing a particular V beta demonstrates that NC is a SAg in mice. T cells, especially CD4+ T cells, are an essential factor in host resistance to rabies virus and also in the pathophysiology of paralysis; thus, we postulate that a rabies virus component, which stimulates T cells, such as a SAg, may increase virus immunopathogenicity. To evaluate this hypothesis, we compared the course of rabies in adult BALB/c lacking V beta 6, 7, 8.1, and 9 T cells and in normal BALB/c. Immune-related paralysis was decreased in BALB/c missing the NC target V beta T cells. Transfer of V beta 6 but not of V beta 8.1-3 T cells into recipient mice lacking V beta 6, 7, 8.1, and 9 allowed the immune-related paralysis to evolve. Taken together, these results strongly support the hypothesis that T cells expressing rabies SAg-specific V beta 6 T cells, are involved in the genesis of the immunopathology that is characteristic of paralytic rabies.

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