What are the roles of T cells and B cells in the immune response and how are they affected by immunosuppressive medications like prednisone (corticosteroid) and rituximab (anti-CD20 monoclonal antibody)?

T Cells and B Cells: Roles in Immune Response and Effects of Immunosuppressive Medications

Core Functions in Immune Response

T cells and B cells constitute the two critical arms of adaptive immunity, with T cells primarily mediating cellular immune responses through direct cytotoxic mechanisms and cytokine production, while B cells produce neutralizing antibodies that clear circulating pathogens and prevent viral spread. 1

T Cell Functions

• CD4+ and CD8+ T cells directly target infected cells for elimination via cytopathic mechanisms 1
• Suppress viral replication through non-cytopathic cytokine-mediated pathways, predominantly via interferons 1
• Require interleukin production for proper activation and proliferation 1
• Function as the predominant mechanism in suppressing viral replication, particularly in hepatitis B virus control 1

B Cell Functions

• Differentiate into plasmocytes that produce neutralizing antibodies to clear circulating viruses 1
• Function as antigen-presenting cells, contributing to T-cell activation 2
• Produce effector cytokines that modulate the local immune environment 2
• Play a previously unappreciated but critical role in immune control, as evidenced by viral reactivation when B-cell immunity is suppressed 1

Effects of Prednisone (Corticosteroids)

Prednisone suppresses both T-cell and B-cell immunity by inhibiting interleukin production essential for lymphocyte proliferation, with effects being dose-dependent and clinically significant at doses above 10 mg daily. 1, 3

Mechanisms of Immunosuppression

• Inhibits production of interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-6 (IL-6), tumor necrosis factor (TNF), and gamma interferon 3
• Blocks antigen-induced T-cell proliferation by suppressing cytokine production necessary for immune activation 3
• Diminishes lymphocyte proliferation through general cytotoxic effects 1
• Suppresses cell-mediated immunity broadly across immune functions 1

Clinical Impact on Immune Function

• Doses of prednisolone higher than 10 mg daily (or equivalent doses of other corticosteroids) impair vaccine response 1
• Increases viral replication through direct effects on viral mechanisms and by inhibiting host immune response 3
• Can worsen viral disease or increase the chance of chronic infection 3
• Increases susceptibility to opportunistic infections including fungal, viral, and bacterial pathogens 3, 4

Practical Considerations

• Live attenuated vaccines should be avoided in patients receiving corticosteroid therapy 3
• Prophylaxis against Pneumocystis jirovecii pneumonia should be considered in patients receiving prednisone equivalent of ≥20 mg/day for 4 or more weeks 3
• Tapering the dose around the time of vaccination is necessary when doses exceed 10 mg daily 1

Effects of Rituximab (Anti-CD20 Monoclonal Antibody)

Rituximab causes near-complete B-cell depletion for up to 6 months after therapy by targeting CD20 on B-lymphocyte surfaces, with the majority of patients showing complete B-cell recovery by 1 year, though prolonged depletion and hypogammaglobulinemia can occur. 1, 5

Mechanism of B-Cell Depletion

• Targets CD20 antigen expressed on pre-B and mature B-lymphocytes 5
• Mediates B-cell lysis through complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) 5
• Causes CD20 to cap at the B-cell surface, recruiting other proteins and polarizing the microtubule organizing center, which augments NK-cell-mediated killing by 60% 6
• Results in near-complete depletion (CD19 counts below 20 cells/µL) within 2 weeks after the first dose 5

Timeline of B-Cell Depletion and Recovery

• B-cell depletion persists for at least 6 months in the majority of patients 1, 5
• B-cell recovery begins at approximately 6 months post-treatment 5
• Median B-cell levels return to normal by 12 months following completion of treatment 5
• A small proportion (~4%) experience prolonged peripheral B-cell depletion lasting more than 3 years 5

Impact on Immunoglobulin Levels

• Total serum immunoglobulin levels (IgM, IgG, IgA) are reduced at 6 months, with greatest change in IgM 5
• During repeated rituximab treatment, 23.3% of patients experience decreases in IgM, 5.5% in IgG, and 0.5% in IgA below the lower limit of normal 5
• Prolonged B-cell depletion and hypogammaglobulinemia may occur in some patients 1

Effects on T Cells

• Rituximab depletes not only B cells but also CD20+ T cells from peripheral blood 7, 8
• CD20+ T cells represent 0.1-6.8% of peripheral blood T cells in healthy individuals 8
• These CD20+ T cells are functionally characterized by constitutive cytokine production (IL-1β and TNF-α), low proliferative capacity, high activation state, and enhanced susceptibility to apoptosis 8
• CSF B-cell depletion is associated with reduction in CSF T cells as well 7
• Despite B-cell depletion, ex vivo T-cell proliferation responses remain intact 9

Vaccination Considerations with Rituximab

• Vaccination within the first 6 months after anti-CD20 therapy is generally discouraged because a functioning B-cell compartment is required for adequate immune response 1
• Within the first year after anti-CD20 therapy, assessment of antibody titers and revaccination if indicated might achieve protective antibody levels despite diminished immune response 1
• Administration of a second booster vaccine (particularly for seasonal influenza) significantly increases humoral immune response after anti-CD20 therapy 1
• Rituximab reduces response to pneumococcal and tetanus vaccines, though the degree of reduction is inconsistent between studies 1

Clinical Implications for Viral Reactivation

• The compelling evidence of viral reactivation following B-cell suppression highlights that B cells play a previously unappreciated role in immune control beyond antibody production 1
• B lymphocytes may exert additional functions in suppressing viral replication beyond producing neutralizing antibodies 1
• Hepatitis B virus reactivation can occur due to loss of B-cell-mediated immune control 1