Fully Functional Memory CD8 T Cells in the Absence of CD4 T Cells

Marzo, Amanda L.; Vezys, Vaiva; Klonowski, Kimberly D.; Lee, Seung Joo; Muralimohan, Guruprasaadh; Moore, Meagan W.; Tough, David F.; Lefrançois, Leo

doi:10.4049/jimmunol.173.2.969

Cited by 113 publications

(145 citation statements)

References 42 publications

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“…For example, CD8 activation by vesicular stomatitis virus in the absence of CD4 help, although quantitatively reduced, resulted in a comparable memory response. It was qualitatively similar to CD4 help in CD8 activation, as assessed by cell proliferation, cytokine production, and cytolytic activity (32). In allograft settings, alloreactive-transgenic CD8 T cells also differentiated into fully functional memory cells in the absence of CD4 T cells (25).…”

Section: Discussionmentioning

confidence: 61%

“…However, controversy exists as to the timing of CD4 help during CD8 activation, and the nature of helpless memory CD8 T cell defects (28,31). Cases of functional CD8 memory generation and response independent of CD4 help have also been reported (25,32). For example, CD8 activation by vesicular stomatitis virus in the absence of CD4 help, although quantitatively reduced, resulted in a comparable memory response.…”

Section: Discussionmentioning

confidence: 99%

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Defective Alloreactive CD8 T Cell Function and Memory Response in Allograft Recipients in the Absence of CD4 Help

Zhai

Wang

et al. 2007

The Journal of Immunology

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We have shown that alloreactive CD8 T cell activation may proceed via CD4-dependent and CD4-independent pathways, and that CD8 T cell activation in Ag-primed animals is independent of CD154 costimulation. In this report, we further analyzed the activation and function of alloreactive CD8 CTL effectors in CD4 knockout (KO) skin/cardiac allograft recipients. FACS analysis showed that alloreactive CD8 T cells were activated at a significantly reduced level in CD4 KO mice. Importantly, these helpless CD8 T cells failed to develop CD154 blockade resistance following reactivation by the same alloantigen, indicative of defective memory formation. Only transient CD4 help was required, as short-term CD4 blockade at the time of first skin graft challenge only delayed alloreactive CD8 activation, without affecting the CD8 T cell memory response to a second skin graft. Moreover, postoperative CD4 blockade had no effect on alloreactive CD8 activation. Alloreactive CD8 cells generated in the absence of CD4 help exhibited decreased effector responses. Interestingly, intragraft induction of T cell-targeted chemokines early after transplant was also dependent on CD4 help, as the induction kinetics of CXCL9 and CCL5 in CD4 KO recipients was significantly delayed, coupled with similarly delayed infiltration by CD3/CD8 cells. Remarkably, helpless CD8 cells ultimately entering the graft still displayed significantly diminished T cell effector molecules (IFN-γ, granzyme B). Thus, CD4 help is critical for alloreactive CD8 activation, function, and memory formation.

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Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Defective Alloreactive CD8 T Cell Function and Memory Response in Allograft Recipients in the Absence of CD4 Help

Zhai

Wang

et al. 2007

The Journal of Immunology

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“…The consensus from several reports now appears to be that CD8 ϩ T cell responses are more dependent on CD4 ϩ T cells in cases of immunization with weaker immunogens (36 -38), or when the Ag amounts are limiting (39). Indeed, more recently, it was shown that the requirement for CD4 ϩ T cell help was not a property intrinsic to the CD8 ϩ memory T cells, but was linked to the infectious agent, and even in cases in which the immunogen was weak and the primary CD4 ϩ T cell response was minimal, the CD8 ϩ memory T cells produced mounted a robust recall response (38). This view resonates with our analysis of BCG-OVA infection model as being a weak immunogen, inducing a CD4 ϩ T cell-dependent CD8 ϩ T cell memory, which is highly protective in vivo.…”

Section: Discussionmentioning

confidence: 99%

Reducing the Stimulation of CD8+ T Cells during Infection with Intracellular Bacteria Promotes Differentiation Primarily into a Central (CD62LhighCD44high) Subset

Faassen

Saldanha

Gilbertson

et al. 2005

The Journal of Immunology

105

101

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During infection with lymphocytic choriomeningitis virus, CD8+ T cells differentiate rapidly into effectors (CD62LlowCD44high) that differentiate further into the central memory phenotype (CD62LhighCD44high) gradually. To evaluate whether this CD8+ T cell differentiation program operates in all infection models, we evaluated CD8+ T cell differentiation during infection of mice with recombinant intracellular bacteria, Listeria monocytogenes (LM) and Mycobacterium bovis (BCG), expressing OVA. We report that CD8+ T cells primed during infection with the attenuated pathogen BCG-OVA differentiated primarily into the central subset that correlated to reduced attrition of the primed cells subsequently. CD8+ T cells induced by LM-OVA also differentiated into central phenotype cells first, but the cells rapidly converted into effectors in contrast to BCG-OVA. Memory CD8+ T cells induced by both LM-OVA as well as BCG-OVA were functional in that they produced cytokines and proliferated extensively in response to antigenic stimulation after adoptive transfer. During LM-OVA infection, if CD8+ T cells were guided to compete for access to APCs, then they received reduced stimulation that was associated with increased differentiation into the central subset and reduced attrition subsequently. Similar effect was observed when CD8+ T cells encountered APCs selectively during the waning phase of LM-OVA infection. Taken together, our results indicate that the potency of the pathogen can influence the differentiation and fate of CD8+ T cells enormously, and the extent of attrition of primed CD8+ T cells correlates inversely to the early differentiation of CD8+ T cells primarily into the central CD8+ T cell subset.

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“…We showed that although their was a larger requirement for CD4 + T-cell help during the primary response in case of immunization with DC transduced ex vivo compared to direct administration of lentiviral vectors, CD4 + T-cell depletion strongly reduced the capacity to mount a recall CTL response in both cases. 104 Interestingly, Marzo et al 131 showed that in the case of a Lentiviral vectors in cancer immunotherapy K Breckpot et al VSV infection, a functional CD8 + T-cell memory response can be generated in the absence of CD4 + T cells, this in contrast to an infection with Listeria monocytogenes. These authors suggest that the difference might be due to the fact that VSV can directly infect DC whereas LM needs to be cross-presented.…”

Section: Immunogenicity Of Lentiviral Vectorsmentioning

confidence: 99%

Lentiviral vectors for cancer immunotherapy: transforming infectious particles into therapeutics

2007

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Lentiviral vectors have emerged as promising tools for both gene therapy and immunotherapy purposes. They exhibit several advantages over other viral systems in that they are less immunogenic and are capable of transducing a wide range of different cell types, including dendritic cells (DC). DC transduced ex vivo with a whole range of different (tumor) antigens were capable of inducing strong antigen-specific T-cell responses, both in vitro and in vivo. Recently, the administration of lentiviral vectors in vivo has gained substantial interest as an alternative method for antigenspecific immunization. This method offers a number of advantages over DC vaccines as the same lentivirus can in principle be used for all patients resulting in a significantly reduced cost and requirement for considerably less expertise for the generation and administration of lentiviral vaccines. By selectively targeting lentiviral vectors to, or restricting transgene expression in certain cell types, selectivity, safety and efficacy can be further improved. This review will focus on the use of direct administration of lentiviral vectors encoding tumor-associated antigens (TAA) for the induction of tumor-specific immune responses in vivo, with a special focus on problems related to the generation of large amounts of highly purified virus and specific targeting of antigenpresenting cells (APC).

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Fully Functional Memory CD8 T Cells in the Absence of CD4 T Cells

Cited by 113 publications

References 42 publications

Defective Alloreactive CD8 T Cell Function and Memory Response in Allograft Recipients in the Absence of CD4 Help

Defective Alloreactive CD8 T Cell Function and Memory Response in Allograft Recipients in the Absence of CD4 Help

Reducing the Stimulation of CD8+ T Cells during Infection with Intracellular Bacteria Promotes Differentiation Primarily into a Central (CD62LhighCD44high) Subset

Lentiviral vectors for cancer immunotherapy: transforming infectious particles into therapeutics

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