CD4-deficient T helper cells are capable of supporting somatic hypermutation and affinity maturation of germinal center B cells

Classical CD4+ and CD8+ T cells recognize Ag presented by MHC class II (MHCII) and MHC class I (MHCI), respectively. However, our results show that CD4−/− mice mount a strong, readily detectable CD8+ T cell response to MHCII-restricted epitopes after a primary bacterial or viral infection. These MHCII-restricted CD8+CD4− T cells are more similar to classical CD8+ T cells than to CD4+ T cells in their expression of effector functions during a primary infection, yet they also differ from MHCI-restricted CD8+ T cells by their inability to produce high levels of the cytolytic molecule granzyme B. After resolution of a primary infection, epitope-specific MHCII-restricted T cells in CD4−/− mice persist for a long period of time as memory T cells. Surprisingly, upon reinfection the secondary MHCII-restricted response in CD4−/− mice consists mainly of CD8−CD4− T cells. In contrast to CD8+ T cells, MHCII-restricted CD8−CD4− T cells are capable of producing IL-2 in addition to IFN-γ and thus appear to have attributes characteristic of CD4+ T cells rather than CD8+ T cells. Therefore, MHCII-restricted T cells in CD4−/− mice do not share all phenotypic and functional characteristics with MHCI-restricted CD8+ T cells or with MHCII-restricted CD4+ T cells, but, rather, adopt attributes from each of these subsets. These results have implications for understanding thymic T cell selection and for elucidating the mechanisms regulating the peripheral immune response and memory differentiation.

Section: Cd4supporting

confidence: 85%

Section: D4mentioning

confidence: 99%

Functional Characterization of MHC Class II-Restricted CD8+CD4− and CD8−CD4− T Cell Responses to Infection in CD4−/− Mice

Pearce

Shedlock

Shen

2004

“…This double-negative (DN) T cell population can produce IFN-␥ upon parasite challenge (25), can mediate Ab class switching (25,37), can support somatic hypermutation and affinity maturation of germinal center B cells (29), and is known to produce IL-2 upon ex vivo stimulation (38). Based on these observations, we speculate that this DN TCR␣␤ ϩ cell population could be responsible for the polyclonal B cell activation seen in CD4KO mice.…”

Section: Discussionmentioning

confidence: 92%

“…CD4KO mice have impaired humoral responses and produce significantly reduced levels of Abs to T-dependent Ags. In a recent study, it was shown that CD4-deficient mice formed 30 -40% fewer germinal centers in the spleen, compared with wild-type controls (29). The role of CD4 T cells in autoimmunity has been explored using the MRL/lpr mice.…”

Section: Discussionmentioning

confidence: 99%

The Role of Host CD4 T Cells in the Pathogenesis of the Chronic Graft-versus-Host Model of Systemic Lupus Erythematosus

Choudhury

Maldonado

Cohen

et al. 2005

Systemic lupus erythematosus is characterized by production of autoantibodies and glomerulonephritis. The murine chronic graft-vs-host (cGVH) model of systemic lupus erythematosus is induced by allorecognition of foreign MHC class II determinants. Previous studies have shown that cGVH could not be induced in CD4 knockout (CD4KO) mice. We have further explored the role of host CD4 T cells in this model. Our studies now show that B cells in CD4KO mice have intrinsic defects that prevent them from responding to allohelp. In addition, B cells in CD4KO mice showed phenotypic differences compared with congeneic C57BL/6 B cells, indicating some degree of in vivo activation and increased numbers of cells bearing a marginal zone B cell phenotype. The transfer of syngeneic CD4 T cells at the time of initiation of cGVH did not correct these B cell abnormalities; however, if CD4 T cells were transferred during the development and maturation of B cells, then the B cells from CD4KO mice acquire the ability to respond in cGVH. These studies clearly indicate that B cells need to coexist with CD4 T cells early in their development to develop full susceptibility to alloactivation signals.

“…The frequencies of specific AFCs from both splenocytes and bone marrow (BM) cells were estimated by ELISPOT assay as described (27,28). In brief, nitrocellulose filters were coated with 5 g/ml HA or NP in PBS at 4 o C overnight, and then blocked with 10% FCS in PBS.…”

Section: Measurement Of Ab-forming Cells (Afcs) By Elispot Assaymentioning

confidence: 99%

Rectification of Age-Associated Deficiency in Cytotoxic T Cell Response to Influenza A Virus by Immunization with Immune Complexes

Zheng¹,

Zhang

He³

et al. 2007

Self Cite

Decline in cellular immunity in aging compromises protection against infectious diseases and leads to the increased susceptibility of the elderly to infection. In particular, Ag-specific cytotoxic T lymphocyte (CTL) response against virus is markedly reduced in an aged immune system. It is of great importance to explore novel strategy in eliciting effective antiviral CTL activity in the elderly. In this study, the efficacy and mechanisms of immunization with immune complexes in overcoming age-associated deficiency in cellular immunity were investigated. In this study, we show that the severely depressed CTL response to influenza A in aged mice can be significantly restored by immunization with immune complexes consisting of influenza A virus and mAb to influenza A nucleoprotein. The main mechanisms underlying this recovery of CTL response induced by immune complex immunization in aged mice are enhanced dendritic cell function and elevated production of IFN-γ in both CD4+ Th1 and CD8+ CTLs. Thus, these results demonstrate that immune complex immunization may represent a novel strategy to elicit effective virus-specific cytotoxic response in an aged immune system, and possibly, to overcome age-related immune deficiency in general.