CD28 Is Required for Optimal Induction, but Not Maintenance, of Vaccine-Induced Immunity toBlastomyces dermatitidis

Abstract

Cellular immunity mediated by T lymphocytes, in particular CD4؉ and CD8 ؉ type 1 cells, is the main defense against pathogenic fungi. Here, CD28-deficient (CD28 ؊/؊ ) mice were used to study the role of costimulation for the generation and maintenance of T-cell-mediated, type 1 cytokine-dependent mechanisms of vaccine immunity to Blastomyces dermatitidis infection. Disruption of CD28 costimulation reduced the number of type 1 CD4 and CD8 cells generated and impaired resistance to infection. Type 1 T-cell subsets generated in vaccinated CD28 ؊/؊ mice were durable and protected mice for at least 3 months after vaccination. Our findings suggest that CD28 is required for the induction of optimal, protective T-cell responses to B. dermatitidis infection but may be dispensable for the maintenance of T-cell memory.Protective immunity to infections with endemic fungi, including Blastomyces dermatitidis, is thought to require type 1-dependent cell-mediated immunity (CMI) responses (10,11,33,35) and can be mediated by both vaccine-induced CD4 ϩ (35) and CD8 ϩ T cells (34) that produce type 1 cytokines, particularly gamma interferon (IFN-␥) and tumor necrosis factor alpha (TNF-␣). To uncover the molecular requirement that lead to effective generation and maintenance of memory T cells, we investigated the role of B7:CD28 costimulation for the activation of CD4 and CD8 T cells in vaccine-induced immunity to B. dermatitidis infection.It is now accepted that the engagement of the T-cell receptor (TCR) by peptide/major histocompatibility complex (signal 1) is generally not sufficient to trigger a T-cell response and that ligation of a costimulatory receptor(s) (signal 2) is required (17,19,24,31). Indeed, signaling via the TCR alone can induce a state of anergy in naive CD4 ϩ T cells in certain situations (4, 5). The most-studied costimulatory molecules are B7-1 (CD80) and B7-2 (CD86), which bind to the counterreceptors CD28 and CTLA-4 at the T-cell surface. The B7-1/ B7-2:CD28/CTLA-4 costimulatory pathway has received considerable attention as a regulatory control point in T-cell responses. The low levels of B7-1 and B7-2 on immature antigen-presenting cells (APC) are upregulated after activation and interact with positive (CD28) or negative (CTLA-4) receptors on T cells. Both B7 molecules are considered essential for induction of major histocompatibility complex class IIrestricted T-cell responses (4). In support of this view, CD4 T-cell responses to lymphocytic choriomeningitis virus (9, 20), herpes simplex virus type 1 (13), and influenza virus (3) are greatly reduced in CD28 Ϫ/Ϫ mice. Conversely, parasitic infection with Leishmania major (7), Toxoplasma gondii (30), and Heligmosomoides polygyrus (15) activates CD4 cells independently of CD28/B7 interaction.The role of B7 costimulation in the initiation of CD8 responses in vivo is less clear. In cases where the CD8 response occurs through a CD4-dependent pathway of APC activation, it is held that APC conditioning involves costimulatory signaling via CD40-CD40L and B7-CD28. ...

Multiple Immune Factors Are Involved in Controlling Acute and Chronic Chikungunya Virus Infection

“…2C ), by which time the control µMT mice would presumably have generated CHIKV-specific T cells in response to the infection. Given unadjuvanted, killed, whole-virus vaccines are generally poor at inducing CD8 T cells [59] and CD4 T cell recall responses usually peak around day 4 [60] , this experiment provides further support for an antibody-independent role of CD4 T cells in CHIKV viraemia suppression.…”

CD28 Exerts Protective and Detrimental Effects in a Pulmonary Model of Paracoccidioidomycosis

“…As has been shown in murine candidiasis and aspergillosis (54,55), our study demonstrates that in pulmonary PCM, CD28 signaling leads to Treg development, but in the absence of CD28 costimulation, production of IL-2 was impaired, and the commitment of T lymphocytes to the regulatory phenotype was practically abolished. Interestingly, with the opportunistic pathogen Candida albicans, CD28-dependent Treg cells were needed to restrain pathogen clearance, to control inflammatory reactions, and to ensure immunoprotection against a secondary challenge, but with Blastomyces dermatitidis, a primary pathogen, vaccineinduced memory was shown to be CD28 independent (54,84). In our studies, WT mice developed a canonical pattern of immunity in which the activation process was tightly regulated by deactivation mechanisms that controlled excessive inflammatory reactions and consequent tissue damage.…”

“…In primary and opportunistic fungal infections, CD28 costimulation controls protective immunity, the expansion and function of regulatory T cells, and the intensity of inflammatory reactions (5,54,55,66,84). Because CD28 is critical for T-cell activation in fungal infections, we investigated its role in a murine model of P. brasiliensis infection.…”

Blastomycosis

“…Recent vaccine studies in animal models have shown that CMI is mediated by both vaccine-induced CD4 + [37] and CD8 + T cells [38] which produce type-1 cytokines such as gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α). In addition, the CD28 + T cell receptor has been shown to be required for the induction of protective T cell responses to B. dermatitidis infection [39]. CD4 + cells require interleukin-12 (IL-12) for the development of CMI while CD8 + cells were less dependent on IL-12 for this process [40].…”